31471
2010
2010
eng
article
1
--
--
--
Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low- renin and high-renin models
Objectives The nitric oxide-soluble guanylate cyclase (sGC)-cGMP signal transduction pathway is impaired in different cardiovascular diseases, including pulmonary hypertension, heart failure and arterial hypertension. Riociguat is a novel stimulator of soluble guanylate cyclase (sGC). However, little is known about the effects of sGC stimulators in experimental models of hypertension. We thus investigated the cardio-renal protective effects of riociguat in low- renin and high-renin rat models of hypertension. Methods The vasorelaxant effect of riociguat was tested in vitro on isolated saphenous artery rings of normal and nitrate tolerant rabbits. The cardiovascular in-vivo effects of sGC stimulation were evaluated in hypertensive renin-transgenic rats treated with the nitric oxide-synthase inhibitor N- nitro-L-arginine methyl ester (L-NAME) (high-renin model) and in rats with 5/6 nephrectomy (low-renin model). Results In both animal models, riociguat treatment improved survival and normalized blood pressure. Moreover, in the L-NAME study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight and lower cardiac interstitial fibrosis, and reduced renal target organ damage as indicated by lower plasma creatinine and urea, less glomerulosclerosis and less renal interstitial fibrosis. In the 5/6 nephrectomy study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight, lower myocyte diameter and lower arterial media/lumen ratio, and reduced renal target organ damage as indicated by improved creatinine clearance and less renal interstitial fibrosis. Conclusion We demonstrate for the first time that the novel sGC stimulator riociguat shows in two independent models of hypertension a potent protection against cardiac and renal target organ damage. J Hypertens 28: 1666-1675 (c) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
http://journals.lww.com/jhypertension/pages/default.aspx
10.1097/Hjh.0b013e32833b558c
0263-6352
allegro:1991-2014
10107775
Journal of hypertension. - ISSN 0263-6352. - 28 (2010), 8, S. 1666 - 1675
Yuliya Sharkovska
Philipp Kalk
Bettina Lawrenz
Michael Godes
Linda Sarah Hoffmann
Kathrin Wellkisch
Sandra Geschka
Katharina Relle
Berthold Hocher
Johannes-Peter Stasch
Institut für Ernährungswissenschaft
Referiert
32161
2010
2010
eng
article
1
--
--
--
Hyperaldosteronism in Klotho-deficient mice
Klotho is a membrane protein participating in the inhibitory effect of FGF23 on the formation of 1,25- dihydroxyvitamin-D-3 [1,25(OH)(2)D-3]. It participates in the regulation of renal tubular phosphate reabsorption and stimulates renal tubular Ca2+ reabsorption. Klotho hypomorphic mice (klotho(hm)) suffer from severe growth deficit, rapid aging, and early death, events largely reversed by a vitamin D-deficient diet. The present study explored the role of Klotho deficiency in mineral and electrolyte metabolism. To this end, klothohm mice and wild-type mice (klotho(+/+)) were subjected to a normal (D+) or vitamin D-deficient (D-) diet or to a vitamin D-deficient diet for 4 wk and then to a normal diet (D-/+). At the age of 8 wk, body weight was significantly lower in klotho(hm)D(+) mice than in klotho(+/ +)D(+) mice, klotho(hm)D(-) mice, and klotho(hm)D(-/+) mice. Plasma concentrations of 1,25(OH)(2)D-3, adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), and aldosterone were significantly higher in klotho(hm)D(+) mice than in klotho(+/+)D(+) mice. Plasma volume was significantly smaller in klotho(hm)D(-/+) mice, and plasma urea, Ca2+, phosphate and Na+, but not K+ concentrations were significantly higher in klotho(hm)D(+) mice than in klotho(+/+)D(+) mice. The differences were partially abrogated by a vitamin D-deficient diet. Moreover, the hyperaldosteronism was partially reversed by Ca2+-deficient diet. Ussing chamber experiments revealed a marked increase in amiloride-sensitive current across the colonic epithelium, pointing to enhanced epithelial sodium channel (ENaC) activity. A salt-deficient diet tended to decrease and a salt-rich diet significantly increased the life span of klotho(hm)D(+) mice. In conclusion, the present observation disclose that the excessive formation of 1,25(OH)(2)D-3 in Klotho-deficient mice results in extracellular volume depletion, which significantly contributes to the shortening of life span.
http://ajprenal.physiology.org/
10.1152/ajprenal.00233.2010
1931-857X
allegro:1991-2014
10108515
American journal of physiology : renal physiology. - ISSN 1931-857X. - 299 (2010), 5, S. F1171 - F1177
Stephanie S. Fischer
Daniela S. Kempe
Christina B. Leibrock
Rexhep Rexhepaj
Balasaheb Siraskar
Krishna M. Boini
Teresa F. Ackermann
Michael Foeller
Berthold Hocher
Kevin P. Rosenblatt
Makoto Kuro-o
Florian Lang
Institut für Ernährungswissenschaft
Referiert
32163
2010
2010
eng
article
1
--
--
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Endothelin B receptor stimulation inhibits suicidal erythrocyte death
Endothelins (ETs), potent endothelium-derived mediators, stimulate formation of nitric oxide, which, in turn, protects against suicidal erythrocyte death or eryptosis, characterized by phosphatidylserine exposure at the erythrocyte surface and triggered by increase in cytosolic Ca2+ ([Ca2+](i)). The present study explored whether the ET1- receptor ETB influences suicidal erythrocyte death. To this end, [Ca2+](i) (Fluo3-fluorescence) and phosphatidylserine exposure (annexin V-binding) were determined utilizing FACS analysis. Energy depletion increased [Ca2+]i and phosphatidylserine-exposure, effects significantly blunted by ET1 (IC50 approximate to 100 nM) and the ETB receptor- agonist sarafotoxin 6c (IC50 approximate to 10 nM) but not by ET2 and ET3. ET1 and sarafotoxin significantly delayed the kinetics of suicidal erythrocyte death following energy depletion. ETB stimulation did not blunt the effect of Ca2+- ionophore ionomycin (1 mu M) on phosphatidylserine exposure. The in vivo significance was tested using rescued ETB- knockout (etb(-/-)) and wild-type (etb(+/+)) mice. The number of phosphatidylserine-exposing erythrocytes, of reticulocytes and spleen size were significantly larger in etb(-/-) mice than in etb(+/+)-mice. The etb(-/-) erythrocytes were more susceptible to the eryptotic effect of oxidative stress and more rapidly cleared from circulating blood than etb(+/+) erythrocytes. Finally, the spleens from etb(-/-) mice were enlarged and contained markedly more phosphatidylserine- exposing erythrocytes than spleens from etb(+/+) mice. The observations disclose a novel function of ET1, i. e., protection from suicidal erythrocyte death.
http://www.fasebj.org/
10.1096/Fj.10-159483
0892-6638
allegro:1991-2014
10108517
The FASEB journal. - ISSN 0892-6638. - 24 (2010), 9, S. 3351 - 3359
Michael Foeller
Hasan Mahmud
Syed M. Qadri
Shuchen Gu
Manuel Braun
Diwakar Bobbala
Berthold Hocher
Florian Lang
Institut für Ernährungswissenschaft
Referiert
32235
2010
2010
eng
article
1
--
--
--
Adenosine A1 receptor antagonists in clinical research and development
Selective adenosine A1 receptor antagonists targeting renal microcirculation are novel pharmacologic agents that are currently under development for the treatment of acute heart failure as well as for chronic heart failure. Despite several studies showing improvement of renal function and/or increased diuresis with adenosine A1 antagonists, particularly in chronic heart failure, these findings were not confirmed in a large phase III trial in acute heart failure patients. However, lessons can be learned from these and other studies, and there might still be a potential role for the clinical use of adenosine A1 antagonists. We review the role of adenosine A1 receptors in the regulation of renal function, and emerging data regarding the safety and efficacy of A1 adenosine receptor antagonists based on all available completed and reported clinical trials using A1 adenosine receptor antagonists. The majority of trials were done in heart failure patients. However, there is clear clinical evidence for a role of this new class in hepatorenal syndrome, hypotension on dialysis, and radiocontrast media-induced nephropathy.
http://www.nature.com/ki/index.html
10.1038/Ki.2010.204
0085-2538
allegro:1991-2014
10108589
Kidney international. - ISSN 0085-2538. - 78 (2010), 5, S. 438 - 445
Berthold Hocher
Institut für Ernährungswissenschaft
Referiert
36787
2011
2011
eng
275
279
5
6
16
article
Med. Scientific Publ. Holzapfel
München
1
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Dual endothelin-converting enzyme/neutral endopeptidase blockade in rats with D-galactosamine-induced liver failure
Secondary activation of the endothelin system is thought to be involved in toxic liver injury. This study tested the hypothesis that dual endothelin-converting enzyme / neutral endopeptidase blockade might: be able to attenuate acute toxic liver injury.
Male Sprague-Dawley rats were implanted with subcutaneous minipumps to deliver the novel compound SLV338 (10 mg/kg*d) or vehicle. Four days later they received two intraperitoneal injections of D-galactosamine (1.3 g/kg each) or vehicle at an interval of 12 hours. The animals were sacrificed 48 hours after the first injection.
Injection of D-galactosamine resulted in very severe liver injury, reflected by strongly elevated plasma liver enzymes, hepatic necrosis and inflammation, and a mortality rate of 42.9 %. SLV338 treatment did not show any significant effect on the extent of acute liver injury as judged from plasma parameters, hepatic histology and mortality. Plasma measurements of SLV338 confirmed adequate drug delivery. Plasma concentrations of big endothelin-1 and endothelin-1 were significantly elevated in animals with liver injury (5-fold and 62-fold, respectively). Plasma endothelin-1 was significantly correlated with several markers of liver injury. SLV338 completely prevented the rise of plasma big endothelin-1 (p<0.05) and markedly attenuated the rise of endothelin-1 (p = 0.055).
In conclusion, dual endothelin-converting enzyme / neutral endopeptidase blockade by SLV338 did not significantly attenuate D-galactosamine-induced acute liver injury, although it largely prevented the activation of the endothelin system. An evaluation of SLV338 in a less severe model of liver injury would be of interest, since very severe intoxication might not be relevantly amenable to pharmacological interventions.
European journal of medical research : official organ "Deutsche AIDS-Gesellschaft"
0949-2321
wos:2011-2013
WOS:000292524100006
Hocher, B (reprint author), Univ Potsdam, Inst Nutr Sci, Potsdam, Germany., berthold.hocher@charite.de
Abbott Products GmbH
Berthold Hocher
S. Heiden
Karoline von Websky
Jörg Rahnenführer
Philipp Kalk
T. Pfab
eng
uncontrolled
endothelin
eng
uncontrolled
endothelin-converting enzyme
eng
uncontrolled
neutral endopeptidase
eng
uncontrolled
D-galactosamine
eng
uncontrolled
acute liver failure
Institut für Informatik und Computational Science
Referiert
Institut für Informatik
36736
2011
2011
eng
10
7
6
article
PLoS
San Fransisco
1
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--
--
Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive dahl rats
Background: A direct pharmacological stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat (BAY 63-2521), have a dual mode of action: They sensitize sGC to endogenously produced nitric oxide (NO) and also directly stimulate sGC independently of NO. Little is known about their effects on tissue remodeling and degeneration and survival in experimental malignant hypertension.
Methods and Results: Mortality, hemodynamics and biomarkers of tissue remodeling and degeneration were assessed in Dahl salt-sensitive rats maintained on a high salt diet and treated with riociguat (3 or 10 mg/kg/d) for 14 weeks. Riociguat markedly attenuated systemic hypertension, improved systolic heart function and increased survival from 33% to 85%. Histological examination of the heart and kidneys revealed that riociguat significantly ameliorated fibrotic tissue remodeling and degeneration. Correspondingly, mRNA expression of the pro-fibrotic biomarkers osteopontin (OPN), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in the myocardium and the renal cortex was attenuated by riociguat. In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1.
Conclusions: Stimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload. These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions.
PLoS one
10.1371/journal.pone.0021853
1932-6203
wos:2011-2013
e21853
WOS:000292812400018
Geschka, S (reprint author), Bayer HealthCare, Cardiol Res, Wuppertal, Germany., johannes-peter.stasch@bayer.com
Sandra Geschka
Axel Kretschmer
Yuliya Sharkovska
Oleg V. Evgenov
Bettina Lawrenz
Andreas Hucke
Berthold Hocher
Johannes-Peter Stasch
Institut für Ernährungswissenschaft
Referiert
Open Access
36500
2011
2011
eng
9
11
6
article
PLoS
San Fransisco
1
--
--
--
Effects of DPP-4 Inhibitors on the Heart in a Rat Model of Uremic Cardiomyopathy
Background: Uremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD) patients. Glucagon-like peptide-1 (GLP-1) may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4).
Methodology/Principal Findings: In a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin) or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-infinity) in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-infinity) values; 41% and 28% (p=0.0001 and p=0.0324), respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 mu mol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h) in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h) (p=0.01). The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin.
Conclusions/Significance: DPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP). Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment.
PLoS one
10.1371/journal.pone.0027861
1932-6203
wos:2011-2013
e27861
WOS:000297789200032
Chaykovska, L (reprint author), Charite, Inst Pharmacol & Toxicol, Cardiovasc Res Ctr, D-13353 Berlin, Germany., hocher@uni-potsdam.de
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss,
Germany; Boehringer Ingelheim Pharma GmbH
Lyubov Chaykovska
Karoline von Websky
Jan Rahnenführer
Markus L. Alter
Susi Heiden
Holger Fuchs
Frank Runge
Thomas Klein
Berthold Hocher
Institut für Ernährungswissenschaft
Referiert
Open Access
36485
2011
2011
eng
4054
U583
8
12
26
article
Oxford Univ. Press
Oxford
German Diabetes & Dialysis Study I
1
--
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Impact of vitamin A on clinical outcomes in haemodialysis patients
Background. Patients on maintenance haemodialysis treatment experience an excessive risk of cardiovascular disease and mortality. The vitamin A concentration is known to be higher in these patients compared to the general population where elevated vitamin A concentrations are associated with adverse outcome. The impact of vitamin A on morbidity and mortality in end-stage renal disease patients is controversial and is the topic of this study.
Methods. We analysed plasma retinol and retinol-binding protein 4 (RBP4) in 1177 diabetic haemodialysis patients, who participated in the German Diabetes and Dialysis Study (median follow-up 4 years). By Cox regression analyses hazard ratios (HRs) were determined for pre-specified, adjudicated end points according to baseline concentrations.
Results. Patients had a mean age of 66 +/- 8 years, mean retinol and RBP4 concentrations of 3.28 (0.71-7.44) and 4.02 (1.28-10.1) mu mol/L, respectively. Patients with retinol concentrations in the first quartile (<2.6 mu mol/L) had an almost 2-fold increased risk of all-cause mortality compared to patients of the fourth quartile [>3.9 mu mol/L; HR 1.81, 95% confidence interval (CI) 1.43-2.30]. There was a strong association between low retinol and the risk of sudden cardiac death (SCD, HR 2.22, 95% CI 1.41-3.50) and fatal infection (HR 2.19, 95% CI 1.26-3.82). Patients with RBP4 concentrations in the lowest quartile (<3.0 mu mol/L) were more likely to die of any cause (HR 1.43, 95% CI 1.14-1.80), experience SCD (HR 1.97, 95% CI 1.28-3.03) and cardiovascular events (HR 1.43, 95% CI 1.10-1.85).
Conclusion. This large cohort study shows a strong association of low retinol and RBP4 concentrations with SCD and all-cause mortality in diabetic haemodialysis patients.
Nephrology, dialysis, transplantation
10.1093/ndt/gfr171
0931-0509
wos:2011-2013
WOS:000297404000035
Espe, KM (reprint author), Univ Potsdam, Inst Nutr Sci, Potsdam, Germany., espe@uni-potsdam.de
Else-Kroner-Fresenius foundation
Katharina M. Espe
Jens Raila
Andrea Henze
Vera Krane
Florian J. Schweigert
Berthold Hocher
Christoph Wanner
Christiane Drechsler
eng
uncontrolled
haemodialysis
eng
uncontrolled
mortality
eng
uncontrolled
retinol
eng
uncontrolled
retinol-binding protein 4
eng
uncontrolled
sudden death
Institut für Ernährungswissenschaft
Referiert
36939
2011
2011
eng
755
763
9
4
57
article
LIPPINCOTT WILLIAMS & WILKINS
PHILADELPHIA
1
--
--
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Endothelin-Converting Enzyme/Neutral Endopeptidase Inhibitor SLV338
Prevents Hypertensive Cardiac Remodeling in a Blood Pressure-Independent
Manner
Hypertensive heart disease is a major contributor to cardiovascular mortality. Endothelin is a potent vasoconstrictive and profibrotic mediator produced by the endothelin-converting enzyme (ECE), whereas natriuretic peptides, degraded by the neutral endopeptidase (NEP), have diuretic, vasodilatory, and antifibrotic properties. Thus, combined ECE/NEP inhibition may halt hypertensive cardiac remodeling. This study examined effects of SLV338, a novel ECE/NEP inhibitor, on cardiac protection in experimental renovascular hypertension (2-kidney, 1-clip [2K1C]). Male rats were allocated to 5 groups: sham-operated rats, untreated animals with 2K1C, 2K1C animals treated with oral SLV338 (30 and 100 mg/kg per day), and 2K1C animals treated with oral losartan (20 mg/kg per day). Treatment duration was 12 weeks. Blood pressure was assessed every 4 weeks. At study end, hearts were taken for histology/computer-aided histomorphometry/immunohistochemistry. Pharmacological properties of SLV338 are described. SLV338 is a dual ECE/NEP inhibitor, as demonstrated both in vitro and in vivo. In the 2K1C study, losartan lowered blood pressure by <= 46 mm Hg, whereas both dosages of SLV338 had no effect. However, SLV338 (both dosages) completely normalized cardiac interstitial fibrosis, perivascular fibrosis, myocyte diameter, and media: lumen ratio of cardiac arteries, as did losartan. Cardiac transforming growth factor-beta 1 expression was significantly enhanced in untreated 2K1C rats versus controls, whereas treatment with SLV338 and losartan prevented this effect. Taken together, dual ECE/NEP inhibitor SLV338 prevents cardiac remodeling to the same extent as losartan, but in a blood pressure-independent manner, in a rat model of renovascular hypertension. This effect is at least partially mediated via suppression of cardiac transforming growth factor-beta 1 expression. (Hypertension. 2011;57:755-763.)
HYPERTENSION
10.1161/HYPERTENSIONAHA.110.163972
0194-911X
wos:2011-2013
WOS:000288434600022
Hocher, B (reprint author), Univ Potsdam, Inst Nutr Sci, Arthur Scheunert Allee 114-116, D-14558 Potsdam, Germany.
, berthold.hocher@charite.de
Else Kroner-Fresenius Stiftung; Dr Werner Jackstadt Stiftung; Solvay
Pharmaceuticals
Philipp Kalk
Yuliya Sharkovska
Elena Kashina
Karoline von Websky
Katharina Relle
Thiemo Pfab
Markus L. Alter
Philippe Guillaume
Daniel Provost
Katrin Hoffmann
Yvan Fischer
Berthold Hocher
eng
uncontrolled
renovascular hypertension
eng
uncontrolled
cardiac remodeling
eng
uncontrolled
endothelin-converting enzyme
eng
uncontrolled
neutral endopeptidase
eng
uncontrolled
TGF-beta 1
36893
2011
2011
eng
961
970
10
5
29
article
Lippincott Williams & Wilkins
Philadelphia
1
--
--
--
Endothelin-1 overexpression restores diastolic function in eNOS knockout mice
Background The cardiac nitric oxide and endothelin-1 (ET-1) systems are closely linked and play a critical role in cardiac physiology. The balance between both systems is often disturbed in cardiovascular diseases. To define the cardiac effect of excessive ET-1 in a status of nitric oxide deficiency, we compared left ventricular function and morphology in wild-type mice, ET-1 transgenic (ET+/+) mice, endothelial nitric oxide synthase knockout (eNOS(-/-)) mice, and ET(+/+)eNOS(-/-) mice.
Methods and results eNOS(-/-) and ET(+/+)eNOS(-/-) mice developed high blood pressure compared with wild-type and ET+/+ mice. Left ventricular catheterization showed that eNOS(-/-) mice, but not ET(+/+)eNOS(-/-), developed diastolic dysfunction characterized by increased end-diastolic pressure and relaxation constant tau. To elucidate the causal molecular mechanisms driving the rescue of diastolic function in ET(+/+)eNOS(-/-) mice, the cardiac proteome was analyzed. Two-dimensional gel electrophoresis coupled to mass spectrometry offers an appropriate hypothesis-free approach. ET-1 overexpression on an eNOS(-/-) background led to an elevated abundance and change in posttranslational state of antioxidant enzymes (e. g., peroxiredoxin-6, glutathione S-transferase mu 2, and heat shock protein beta 7). In contrast to ET(+/+)eNOS(-/-) mice, eNOS(-/-) mice showed an elevated abundance of proteins responsible for sarcomere disassembly (e. g., cofilin-1 and cofilin-2). In ET(+/+)eNOS(-/-) mice, glycolysis was favored at the expense of fatty acid oxidation.
Conclusion eNOS(-/-) mice developed diastolic dysfunction; this was rescued by ET-1 transgenic overexpression. This study furthermore suggests that cardiac ET-1 overexpression in case of eNOS deficiency causes specifically the regulation of proteins playing a role in oxidative stress, myocytes contractility, and energy metabolism.
Journal of hypertension
10.1097/HJH.0b013e3283450770
0263-6352
1473-5598
wos:2011-2013
WOS:000289276600022
Hocher, B (reprint author), Univ Potsdam, Inst Nutr Sci, D-14558 Nuthetal, Germany., berthold.hocher@charite.de
Deutsche Forschungsgemeinschaft; European Commission
[MEST-CT-2005-020268]
Nicolas Vignon-Zellweger
Katharina Relle
Elodie Kienlen
Markus L. Alter
Patrick Seider
Juliya Sharkovska
Susi Heiden
Philipp Kalk
Karima Schwab
Barbara Albrecht-Kuepper
Franz Theuring
Johannes-Peter Stasch
Berthold Hocher
eng
uncontrolled
cardiovascular diseases
eng
uncontrolled
endothelin
eng
uncontrolled
nitric oxide
Institut für Ernährungswissenschaft
Referiert
36662
2011
2011
eng
1712
1718
7
9
29
article
Lippincott Williams & Wilkins
Philadelphia
1
--
--
--
Low birth weight and elevated head-to-abdominal circumference ratio are associated with elevated fetal glycated serum protein concentrations
Objective To analyze the association between low birth weight, head-to-abdominal circumference ratio, and insulin resistance in early life.
Method and results Glycated serum proteins (GSPs) were quantified at delivery in 612 Chinese mother/child pairs serving as a surrogate of maternal and fetal glycemia. Differential ultrasound examination of the fetal's body (head circumference, biparietal diameter, pectoral diameter, abdominal circumference, and femur length) was done in average 1 week prior to delivery. Multivariable regression analysis considering gestational age at delivery, the child's sex, maternal BMI, maternal age at delivery, maternal body weight, and pregnancyinduced hypertension revealed that fetal GSP was inversely associated with birth weight (R(2) = 0.416; P < 0.001). Fetal GSP was furthermore positively associated with the head-to-abdominal circumference ratio, whereas the maternal GSP was negatively correlated with the offspring's head-to-abdominal circumference ratio (R(2) = 0.285; P = 0.010 and R(2) = 0.261; P = 0.020, respectively). The increased head-to-abdominal circumference ratio in newborns with higher fetal GSP is mainly due to a reduced abdominal circumference rather than reduced growth of the brain.
Conclusion The disproportional intrauterine growth is in line with the concept of so-called brain sparing, a mechanism maintaining the intrauterine growth of the brain at the expense of trunk growth. Our data suggest that the low birth weight phenotype, linked to cardiovascular diseases like hypertension in later life, might be a phenotype of disproportional intrauterine growth retardation and early life insulin resistance.
Journal of hypertension
10.1097/HJH.0b013e328349a2e6
0263-6352
wos:2011-2013
WOS:000293825600007
Hocher, B (reprint author), Univ Potsdam, Inst Nutr Sci, D-14558 Potsdam, Germany., berthold.hocher@charite.de
Hoffmann-La Roche Inc., Basel, Switzerland
Jian Li
Zi-Neng Wang
Ludwig Schlemm
Thiemo Pfab
Xiao-Min Xiao
You-Peng Chen
Berthold Hocher
eng
uncontrolled
disproportional intrauterine growth retardation
eng
uncontrolled
insulin resistance
eng
uncontrolled
low birth weight
eng
uncontrolled
ultrasound
Institut für Ernährungswissenschaft
Referiert
36650
2011
2011
eng
254
261
8
3
12
article
Sage Publ.
London
1
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--
--
Offspring sex determines the impact of the maternal ACE I/D polymorphism on maternal glycaemic control during the last weeks of pregnancy
Hypothesis/Introduction: We recently demonstrated that fetal sex may affect maternal glycaemic control in genetically prone mothers. We tested the hypothesis that fetal sex/fetal Y/X chromosomes might affect maternal glycaemic control during pregnancy depending on the maternal angiotensin converting enzyme (ACE) I/D polymorphism.
Material and methods: One thousand, three hundred and thirty-two Caucasian women without pre-existing diabetes and pre-existing hypertension with singleton pregnancies delivering consecutively at the Charite obstetrics department were genotyped. Glycaemic control was analysed by measuring total glycated haemoglobin at birth. Correction for confounding factors and multiple testing was done.
Results: Maternal ACE I/D polymorphism showed significant interaction with fetal sex concerning maternal total glycated haemoglobin. Total glycated haemoglobin in DD mothers delivering boys was 6.42 +/- 0.70% vs. 6.21 +/- 0.66% in DD mother delivering girls (p < 0.005), whereas the II carrying mothers showed the opposite effect. II mothers delivering a girl had a higher (p = 0.044) total glycated haemoglobin at birth (6.40 +/- 0.80%) compared to II mothers delivering boys (6.21 +/- 0.81%). There was no interaction of the ACE I/D polymorphism and fetal sex with respect to new onset proteinuria, new onset edema and pregnancy-induced hypertension.
Conclusions: Maternal glycaemic control during the last weeks of pregnancy seems to be influenced by an interaction of the ACE I/D genotyp and fetal sex.
Journal of the renin angiotensin aldosterone system
10.1177/1470320310387843
1470-3203
wos:2011-2013
WOS:000294450600016
Hocher, B (reprint author), Charite Mitte, Inst Pharmacol, Cardiovasc Res Ctr, Hessische Str 3-4, D-10115 Berlin, Germany., berthold.hocher@charite.de
Fresenius Foundation
Berthold Hocher
Ludwig Schlemm
Hannah Haumann
Jian Li
Jan Rahnenführer
Florian Guthmann
Christian Bamberg
Philipp Kalk
Thiemo Pfab
You-Peng Chen
eng
uncontrolled
ACE I/D polymorphism
eng
uncontrolled
pregnancy
eng
uncontrolled
fetal sex
eng
uncontrolled
pregnancy induced diabetes
eng
uncontrolled
total glycated hemoglobin
eng
uncontrolled
glycemic control during pregnancy
Institut für Ernährungswissenschaft
Referiert
36989
2011
2011
eng
779
789
11
3
26
article
Oxford Univ. Press
Oxford
1
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--
Endothelin type A and B receptors in the control of afferent and efferent arterioles in mice
Background. Endothelin 1 contributes to renal blood flow control and pathogenesis of kidney diseases. The differential effects, however, of endothelin 1 (ET-1) on afferent (AA) and efferent arterioles (EA) remain to be established.
Methods. We investigated endothelin type A and B receptor (ETA-R, ETB-R) functions in the control of AA and EA. Arterioles of ETB-R deficient, rescued mice [ETB (-/-)] and wild types [ETB(+/+)] were microperfused.
Results. ET-1 constricted AA stronger than EA in ETB (-/-) and ETB(+/+) mice. Results in AA: ET-1 induced similar constrictions in ETB(-/-) and ETB(+/+) mice. BQ-123 (ETA-R antagonist) inhibited this response in both groups. ALA-ET-1 and IRL1620 (ETB-R agonists) had no effect on arteriolar diameter. L-NAME did neither affect basal diameters nor ET-1 responses. Results in EA: ET-1 constricted EA stronger in ETB(+/+) compared to ETB(-/-). BQ-123 inhibited the constriction completely only in ETB(-/-). ALA-ET-1 and IRL1620 constricted only arterioles of ETB(+/+) mice. L-NAME decreased basal diameter in ETB(+/+), but not in ETB(-/-) mice and increased the ET-1 response similarly in both groups. The L-NAME actions indicate a contribution of ETB-R in basal nitric oxide (NO) release in EA and suggest dilatory action of ETA-R in EA.
Conclusions. ETA-R mediates vasoconstriction in AA and contributes to vasoconstriction in EA in this mouse model. ETB-R has no effect in AA but mediates basal NO release and constriction in EA. The stronger effect of ET-1 on AA supports observations of decreased glomerular filtration rate to ET-1 and indicates a potential contribution of ET-1 to the pathogenesis of kidney diseases.
Nephrology, dialysis, transplantation
10.1093/ndt/gfq534
0931-0509
wos:2011-2013
WOS:000287746500006
Patzak, A (reprint author), Charite, Inst Vegetat Physiol, D-13353 Berlin, Germany., andreas.patzak@charite.de
Janice Schildroth
Juliane Rettig-Zimmermann
Philipp Kalk
Andreas Steege
Michael Faehling
Mauricio Sendeski
Alexander Paliege
En Yin Lai
Sebastian Bachmann
Pontus B. Persson
Berthold Hocher
Andreas Patzak
eng
uncontrolled
endothelin
eng
uncontrolled
ETB receptor-deficient mouse
eng
uncontrolled
glomerular arterioles
eng
uncontrolled
renal haemodynamics
Institut für Ernährungswissenschaft
Referiert
36963
2011
2011
eng
8
3
6
article
PLoS
San Fransisco
1
--
--
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Renal effects of the novel selective adenosine A(1) receptor blocker SLV329 in experimental liver cirrhosis in rats
Liver cirrhosis is often complicated by an impaired renal excretion of water and sodium. Diuretics tend to further deteriorate renal function. It is unknown whether chronic selective adenosine A(1) receptor blockade, via inhibition of the hepatorenal reflex and the tubuloglomerular feedback, might exert diuretic and natriuretic effects without a reduction of the glomerular filtration rate. In healthy animals intravenous treatment with the novel A(1) receptor antagonist SLV329 resulted in a strong dose-dependent diuretic (up to 3.4-fold) and natriuretic (up to 13.5-fold) effect without affecting creatinine clearance. Male Wistar rats with thioacetamide-induced liver cirrhosis received SLV329, vehicle or furosemide for 12 weeks. The creatinine clearance of cirrhotic animals decreased significantly (-36.5%, p < 0.05), especially in those receiving furosemide (-41.9%, p < 0.01). SLV329 was able to prevent this decline of creatinine clearance. Mortality was significantly lower in cirrhotic animals treated with SLV329 in comparison to animals treated with furosemide (17% vs. 54%, p < 0.05). SLV329 did not relevantly influence the degree of liver fibrosis, kidney histology or expression of hepatic or renal adenosine receptors. In conclusion, chronic treatment with SLV329 prevented the decrease of creatinine clearance in a rat model of liver cirrhosis. Further studies will have to establish whether adenosine A(1) receptor antagonists are clinically beneficial at different stages of liver cirrhosis.
PLoS one
10.1371/journal.pone.0017891
1932-6203
wos:2011-2013
e17891
WOS:000288219100044
Hocher, B (reprint author), Univ Potsdam, Inst Nutr Sci, Potsdam, Germany., berthold.hocher@charite.de
Solvay Pharmaceuticals (now Abbott Products GmbH)
Berthold Hocher
Susi Heiden
Karoline von Websky
Ayman M. Arafat
Jan Rahnenführer
Markus L. Alter
Philipp Kalk
Dieter Ziegler
Yvan Fischer
Thiemo Pfab
Institut für Ernährungswissenschaft
Referiert
Open Access
37159
2011
2011
eng
507
515
9
7-8
57
article
Clin Lab Publ., Verl. Klinisches Labor
Heidelberg
1
--
--
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Renoprotective effects of combined endothelin-converting enzyme/neutral endopeptidase inhibitor SLV338 in acute and chronic experimental renal damage
Background: Acute kidney injury (AKI) as well as chronic renal failure are associated with a huge mortality/morbidity. However, so far no drugs have been approved for the treatment of acute kidney failure and only a few for the treatment of chronic kidney disease (CKD). We analysed the effect of SLV 338, a neutral endopeptidase (NEP)/endothelin converting enzyme (ECE)-inhibitor in animal models of acute kidney failure as well as chronic renal failure.
Methods: Acute renal failure was induced in male Wistar rats by uninephrectomy and clamping of the remaining kidney for 55 minutes. SLV338 (total dose: 4.9 mg/kg) or vehicle was continuously infused for 2 hours (starting 20 minutes prior to clamping). Sham operated animals served as controls. Plasma creatinine was measured at baseline and day 2 and 8 after renal ischemia-reperfusion.
Hypertensive renal damage was induced in male Sprague Dawley rats by nitric oxide deficiency using L-NAME (50 mg/kg per day, added to drinking water for 4 weeks). One group was treated over the same time period with SLV338 (30 mg/kg per day, mixed with food). Systolic blood pressure was monitored weekly. At study end, urine and blood samples were collected and kidneys were harvested.
Results: Acute renal ischemia-reperfusion caused a 5-fold plasma creatinine elevation (day 2), which was significantly attenuated by more than 50 % in animals treated with SLV338 (p < 0.05). Renal failure was accompanied by a 67 % mortality in vehicle-treated rats, but only 20 % after SLV338 treatment (p = 0.03 compared to sham controls).
Chronic L-NAME administration caused hypertension, urinary albumin excretion, glomerulosclerosis, renal arterial remodelling, and renal interstitial fibrosis. Treatment with SLV338 did not significantly affect blood pressure, but abolished renal tissue damage (interstitial fibrosis, glomerulosclerosis, renal arterial remodelling (p < 0.05 versus L-NAME group in each case).
Conclusions: The dual ECE/NEP inhibitor SLV338 preserves kidney function and reduces mortality in severe acute ischemic renal failure. Moreover, combined ECE/NEP inhibition prevents hypertensive renal tissue damage in a blood pressure independent manner in L-NAME-treated rats.
Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion
1433-6510
wos:2011-2013
WOS:000295251000007
Hocher, B (reprint author), Univ Potsdam, Lehrstuhl Physiol & Pathophysiol Ernahrung, Inst Ernahrungswissensch, Arthur Scheunert Allee 114-116, D-14558 Potsdam, Germany., berthold.hocher@charite.de
Solvay Pharmaceuticals GmbH (now Abbott Products GmbH); Else
Kroner-Fresenius Stiftung; Dr. Werner Jackstadt Stiftung
Yuliya Sharkovska
Philipp Kalk
Karoline von Websky
Katharina Relle
Thiemo Pfab
Markus L. Alter
Yvan Fischer
Berthold Hocher
eng
uncontrolled
Renal failure
eng
uncontrolled
endothelin-converting enzyme
eng
uncontrolled
neutral endopeptidase
Institut für Ernährungswissenschaft
Referiert
37160
2011
2011
eng
651
657
7
9-10
57
article
Clin Lab Publ., Verl. Klinisches Labor
Heidelberg
1
--
--
--
Birthweight and Fetal Glycosylated Hemoglobin at Birth in Newborns Carrying the GLUT1 XbaI Gene Polymorphism
Background: Low birthweight is an independent risk factor of glucose intolerance and type 2 diabetes in later life. Genetically determined insulin resistance and subsequently impaired glucose uptake might explain both reduced fetal growth and elevated blood glucose. The glucose transporter 1 (GLUT!) plays an important role for fetal glucose uptake as well as for maternal-fetal glucose transfer, and it has been associated with insulin resistance in adults. The present study hypothesized that the common fetal GLUT1 XbaI polymorphism might reduce fetal insulin sensitivity and/or glucose supply in utero, thus affecting fetal blood glucose and fetal growth.
Methods: A genetic association study was conducted at the obstetrics department of the Charite University Hospital, Berlin, Germany. 119.1 white women were included after delivery, and all newborns were genotyped for the GLUT1 XbaI polymorphism. Total glycosylated hemoglobin was quantified, serving as a surrogate of glycemia during the last weeks of pregnancy.
Results: The analysis of this large population showed no significant differences in fetal glycosylated hemoglobin or birthweight for the different fetal GLUT1 XbaI genotypes. Only newborns carrying the mutated allele show the previously published inverse association between birthweight and glycosylated hemoglobin.
Conclusions: The results suggest that there is no prenatal effect of the fetal GLUT1 XbaI polymorphism on fetal insulin sensitivity, intrauterine fetal glucose supply or fetal growth. However, the polymorphism seems to modulate the inverse interaction between birthweight and fetal glycemia.
Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion
1433-6510
wos:2011-2013
WOS:000296994300002
Hocher, B (reprint author), Inst Ernahrungswissensch, Lehrstuhl Expt Ernahrungsmad, Arthur Scheunert Allee 114-116, D-14558 Nuthetal, Germany., hocher@uni-potsdam.de
Deutsche Forschungsgemeinschaft (DFG) [Ho1665/5-2]; Else
Kroner-Fresenius-Foundation
Berthold Hocher
Dirk Heimerl
Torsten Slowinski
Michael Godes
Horst Halle
Friedrich Priem
Thiemo Pfab
eng
uncontrolled
GLUT1 XbaI gene polymorphism
eng
uncontrolled
birthweight
eng
uncontrolled
total glycosylated hemoglobin
eng
uncontrolled
insulin resistance
eng
uncontrolled
fetal programming
Institut für Ernährungswissenschaft
Referiert
37061
2011
2011
eng
339
348
10
2
29
article
Lippincott Williams & Wilkins
Philadelphia
1
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--
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1,25-Dihydroxyvitamin D-3-induced aortic calcifications in experimental uremia: up-regulation of osteoblast markers, calcium-transporting proteins and osterix
Background and objective Whether treatment with vitamin D receptor activators contributes to cardiovascular disease in patients with chronic kidney disease is a matter of debate. We studied mechanisms involved in vitamin D-related vascular calcifications in vivo and in vitro.
Methods Aortic calcifications were induced in subtotally nephrectomized (SNX) rats by treatment with a high dose (0.25 mu g/kg per day) of 1,25-dihydroxyvitamin D-3 (calcitriol) given for 6 weeks. Likewise, primary rat vascular smooth muscle cells (VSMCs) were incubated with calcitriol at concentrations ranging from 10(-11) to 10(-7) mol/l. Immunohistochemistry revealed that the aortic expression of osteopontin, osteocalcin and bone sialoprotein was significantly increased in calcitriol-treated SNX rats compared to untreated SNX controls. In addition, aortic expression of the transient receptor potential vanilloid calcium channel 6 (TRPV6) and calbindin D9k was significantly up-regulated by treatment with calcitriol. Furthermore, calcitriol significantly increased expression of the osteogenic transcription factor osterix. In-vitro studies showed similar results, confirming that these effects could be attributed to treatment with calcitriol.
Conclusions High-dose calcitriol treatment induces an osteoblastic phenotype in VSMC both in SNX rats and in vitro, associated with up-regulation of proteins regulating mineralization and calcium transport, and of the osteogenic transcription factor osterix.
Journal of hypertension
10.1097/HJH.0b013e328340aa30
0263-6352
wos:2011-2013
WOS:000285744600024
Querfeld, U (reprint author), Charite, Campus Virchow Klinikum, Dept Pediat Nephrol, Augustenburger Pl 1, D-13353 Berlin, Germany., uwe.querfeld@charite.de
faculty of Charite - Universitatsmedizin Berlin
Hong Zebger-Gong
Dominik Mueller
Michaela Diercke
Dieter Haffner
Berthold Hocher
Steven Verberckmoes
Sven Schmidt
Patrick C. D'Haese
Uwe Querfeld
eng
uncontrolled
calbindin D9k
eng
uncontrolled
calcitriol
eng
uncontrolled
calcium transport
eng
uncontrolled
osteoblast
eng
uncontrolled
osterix
eng
uncontrolled
TRPV5
eng
uncontrolled
TRPV6
eng
uncontrolled
vascular calcification
Institut für Ernährungswissenschaft
Referiert
36996
2011
2011
eng
201
207
7
2
33
article
Routledge, Taylor & Francis Group
Leeds
1
--
--
--
Novel therapy approach in primary stroke prevention simultaneous inhibition of endothelin converting enzyme and neutral endopeptidase in spontaneously hypertensive, stroke-prone rats improves survival
Objectives: Stroke, frequently a consequence of hypertension, is one of the leading causes of death and neurological disabilities worldwide. In the ischemic brain, levels of endothelin-1, one of the most potent vasoconstrictors, are raised. Anti-inflammatory and neuroprotective effects of endothelin antagonists after stroke have been described in literature. Based on these findings, we investigated the protective effect of the endothelin converting enzyme/neutral endopeptidase blocker, SLV 338, in salt-loaded, stroke-prone, spontaneously hypertensive rats.
Methods: Male, 8-week-old spontaneously hypertensive stroke-prone rats were put on a high salt diet and treated with either 30 mg/kg or 100 mg/kg SLV 338 or vehicle for 27 weeks. Blood pressure, neurological outcome, body weight, and mortality were investigated throughout treatment. In weeks 1 and 9, animals were housed in metabolic cages for collection of urinary and blood samples and assessment of salt water and food intake. In weeks 22 and 27, additional blood samples were taken. At the end of the study, all brains were analyzed using magnetic resonance imaging.
Results: SLV 338 was well tolerated in all animals. Neurological outcome and infarct size were similar in all groups. Albuminuria was considerably delayed and the incidence of stroke significantly lowered in treated animals. In spontaneously hypertensive stroke-prone rats, treatment with SLV 338 significantly (P=0.01) improved survival in comparison to the vehicle treated group in a blood pressure-independent manner.
Discussion: Our data in spontaneously hypertensive stroke-prone rats demonstrate that combined endothelin converting enzyme/neutral endopeptidase inhibition could offer a new therapeutic approach for primary stroke prevention and improvement of mortality. The mechanism seems to be blood pressure-independent.
Neurological research : a journal of progress in neurosurgery and neurosciences
10.1179/016164111X12881719352534
0161-6412
wos:2011-2013
WOS:000287516600013
Thoene-Reineke, C (reprint author), Charite, Forsch Einrichtung Expt Med, Campus Benjamin Franklin,Krahmerstr 6-10, D-12207 Berlin, Germany., christa.thoene-reineke@charite.de
Solvay Pharmaceuticals, Hannover, Germany
Christina Wengenmayer
Maxim Krikov
Susanne Mueller
Kristin Lucht
Arno Villringer
Berthold Hocher
Thomas Unger
Christa Thoene-Reineke
eng
uncontrolled
Endothelin
eng
uncontrolled
Hypertension
eng
uncontrolled
Natriuretic peptides
eng
uncontrolled
Stroke
Institut für Ernährungswissenschaft
Referiert
35934
2012
2012
eng
532
+
9
5
44
article
Nature Publ. Group
New York
Cohorts Heart Aging Res Genetic Ep, Early Genetics Lifecourse Epidemio, Early Growth Genetics EGG Consorti
1
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Common variants at 12q15 and 12q24 are associated with infant head circumference
To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.
Nature genetics
10.1038/ng.2238
1061-4036
wos:2011-2013
WOS:000303416300013
Smith, GD (reprint author), Univ Bristol, MRC, Ctr Causal Anal Translat Epidemiol, Sch Social & Community Med, Bristol, Avon, England., Julia.Mackay@bristol.ac.uk; heinrich@helmholtz-muenchen.de; m.jarvelin@imperial.ac.uk; v.jaddoe@erasmusmc.nl; heinrich@helmholtz-muenchen.de; v.jaddoe@erasmusmc.nl; m.jarvelin@imperial.ac.uk; heinrich@helmholtz-muenchen.de; v.jaddoe@erasmusmc.nl; m.jarvelin@imperial.ac.uk
Academy of Finland [104781, 120315, 129269, 1114194, 134839, 129287];
Biocentrum Helsinki; Biocenter, University of Oulu, Finland; British
Heart Foundation; Canadian Institutes of Health Research [MOP 82893];
The Children's Hospital of Philadelphia; Cotswold Foundation; Darlington
Trust; Dutch Asthma Foundation; Dutch Ministry of the Environment;
Erasmus Medical Center Rotterdam; Erasmus University Rotterdam; European
Community [HEALTH-F4-2007-201413]; Exeter National Health Service (NHS)
Research and Development; Fundacio La Marato de TV3 (Televisio de
Catalunya); Helmholtz Zentrum Muenchen; German Research Center for
Environment and Health; Institute of Epidemiology I; Neuherberg;
Instituto de Salud Carlos III [FIS PI081151, PS09/00432]; Institut fur
Umweltmedizinische Forschung (IUF) Dusseldorf; Marien-Hospital Wesel; UK
MRC [G0500539, G0600331, G0600705]; Municipal Health Service Rotterdam;
National Health and Medical Research Council of Australia [403981,
003209]; National Public Health Institute, Helsinki, Finland;
Netherlands Organisation for Scientific Research (NWO); Netherlands
Organisation for Health Research and Development (ZonMw) [SPI
56-464-14192, 904-61-090, 904-61-193, 912-03-031, 480-04-004,
400-05-717]; US NHLBI [5R01HL087679-02, 1RL1MH083268-01]; US NIH
[1R01HD056465-01A1]; Peninsula NIHR Clinical Research Facility; RAINE
Medical Research Foundation; Rotterdam Homecare Foundation; South West
NHS Research and Development; Stichting Astmabestrijding; Stichting
Trombosedienst & Artsenlaboratorium Rijnmond (STAR) Rotterdam; Technical
University Munich; Telethon Institute for Child Health Research;
UFZ-Centre for Environmental Research Leipzig-Halle; University Hospital
Oulu, Finland; University of Bristol; University of Leipzig; Wellcome
Trust [GR069224, 085541/Z/08/Z, WT083431MA, WT088431MA]; Western
Australian DNA Bank; Western Australian Genetic Epidemiology Resource;
ZonMW [21000074]; Dutch Kidney Foundation [C08.2251]; MRC UK [G0500539,
PS0476]; MRC [MRC G0800582]; Netherlands Organisation for Health
Research (ZonMw) [90700303, 916.10159]
H. Rob Taal
Beate St Pourcain
Elisabeth Thiering
Shikta Das
Dennis O. Mook-Kanamori
Nicole M. Warrington
Marika Kaakinen
Eskil Kreiner-Moller
Jonathan P. Bradfield
Rachel M. Freathy
Frank Geller
Monica Guxens
Diana L. Cousminer
Marjan Kerkhof
Nicholas J. Timpson
M. Arfan Ikram
Lawrence J. Beilin
Klaus Bonnelykke
Jessica L. Buxton
Pimphen Charoen
Bo Lund Krogsgaard Chawes
Johan Eriksson
David M. Evans
Albert Hofman
John P. Kemp
Cecilia E. Kim
Norman Klopp
Jari Lahti
Stephen J. Lye
George McMahon
Frank D. Mentch
Martina Mueller-Nurasyid
Paul F. O'Reilly
Inga Prokopenko
Fernando Rivadeneira
Eric A. P. Steegers
Jordi Sunyer
Carla Tiesler
Hanieh Yaghootkar
Monique M. B. Breteler
Stephanie Debette
Myriam Fornage
Vilmundur Gudnason
Lenore J. Launer
Aad van der Lugt
Thomas H. Mosley
Sudha Seshadri
Albert V. Smith
Meike W. Vernooij
Alexandra I. F. Blakemore
Rosetta M. Chiavacci
Bjarke Feenstra
Julio Fernandez-Banet
Struan F. A. Grant
Anna-Liisa Hartikainen
Albert J. van der Heijden
Carmen Iniguez
Mark Lathrop
Wendy L. McArdle
Anne Molgaard
John P. Newnham
Lyle J. Palmer
Aarno Palotie
Annneli Pouta
Susan M. Ring
Ulla Sovio
Marie Standl
Andre G. Uitterlinden
H-Erich Wichmann
Nadja Hawwa Vissing
Charles DeCarli
Cornelia M. van Duijn
Mark I. McCarthy
Gerard H. Koppelman
Xavier Estivill
Andrew T. Hattersley
Mads Melbye
Hans Bisgaard
Craig E. Pennell
Elisabeth Widen
Hakon Hakonarson
George Davey Smith
Joachim Heinrich
Marjo-Riitta Jarvelin
Vincent W. V. Jaddoe
Linda S. Adair
Wei Ang
Mustafa Atalay
Toos van Beijsterveldt
Nienke Bergen
Kelly Benke
Diane J. Berry
Jonathan P. Bradfield
Pimphen Charoen
Lachlan Coin
Diana L. Cousminer
Shikta Das
Oliver S. P. Davis
Paul Elliott
David M. Evans
Bjarke Feenstra
Claudia Flexeder
Tim Frayling
Rachel M. Freathy
Romy Gaillard
Frank Geller
Maria Groen-Blokhuis
Liang-Kee Goh
Monica Guxens
Claire M. A. Haworth
Dexter Hadley
Johannes Hebebrand
Anke Hinney
Joel N. Hirschhorn
John W. Holloway
Claus Holst
Jouke Jan Hottenga
Momoko Horikoshi
Ville Huikari
Elina Hypponen
Carmen Iniguez
Marika Kaakinen
Tuomas O. Kilpelainen
Mirna Kirin
Matthew Kowgier
Hanna-Maaria Lakka
Leslie A. Lange
Debbie A. Lawlor
Terho Lehtimaki
Alex Lewin
Cecilia Lindgren
Virpi Lindi
Reedik Maggi
Julie Marsh
Christel Middeldorp
Iona Millwood
Dennis O. Mook-Kanamori
Jeffrey C. Murray
Michel Nivard
Ellen Aagaard Nohr
Ioanna Ntalla
Emily Oken
Paul F. O'Reilly
Lyle J. Palmer
Kalliope Panoutsopoulou
Jennifer Pararajasingham
Inga Prokopenko
Alina Rodriguez
Rany M. Salem
Sylvain Sebert
Niina Siitonen
Ulla Sovio
Beate St Pourcain
David P. Strachan
Jordi Sunyer
H. Rob Taal
Yik-Ying Teo
Elisabeth Thiering
Carla Tiesler
Andre G. Uitterlinden
Beatriz Valcarcel
Nicole M. Warrington
Scott White
Gonneke Willemsen
Hanieh Yaghootkar
Eleftheria Zeggini
Dorret I. Boomsma
Cyrus Cooper
Xavier Estivill
Matthew Gillman
Struan F. A. Grant
Hakon Hakonarson
Andrew T. Hattersley
Joachim Heinrich
Berthold Hocher
Vincent W. V. Jaddoe
Marjo-Riitta Jarvelin
Timo A. Lakka
Mark I. McCarthy
Mads Melbye
Karen L. Mohlke
George V. Dedoussis
Ken K. Ong
Ewan R. Pearson
Craig E. Pennell
Thomas S. Price
Chris Power
Olli T. Raitakari
Seang-Mei Saw
Andre Scherag
Olli Simell
Thorkild I. A. Sorensen
Nicholas J. Timpson
Elisabeth Widen
James F. Wilson
Wei Ang
Toos van Beijsterveldt
Nienke Bergen
Kelly Benke
Diane J. Berry
Jonathan P. Bradfield
Pimphen Charoen
Lachlan Coin
Diana L. Cousminer
Shikta Das
Paul Elliott
David M. Evans
Tim Frayling
Rachel M. Freathy
Romy Gaillard
Maria Groen-Blokhuis
Monica Guxens
Dexter Hadley
Jouke Jan Hottenga
Ville Huikari
Elina Hypponen
Marika Kaakinen
Matthew Kowgier
Debbie A. Lawlor
Alex Lewin
Cecilia Lindgren
Julie Marsh
Christel Middeldorp
Iona Millwood
Dennis O. Mook-Kanamori
Michel Nivard
Paul F. O'Reilly
Lyle J. Palmer
Inga Prokopenko
Alina Rodriguez
Sylvain Sebert
Ulla Sovio
Beate St Pourcain
Marie Standl
David P. Strachan
Jordi Sunyer
H. Rob Taal
Elisabeth Thiering
Carla Tiesler
Andre G. Uitterlinden
Beatriz Valcarcel
Nicole M. Warrington
Scott White
Gonneke Willemsen
Hanieh Yaghootkar
Dorret I. Boomsma
Xavier Estivill
Struan F. A. Grant
Hakon Hakonarson
Andrew T. Hattersley
Joachim Heinrich
Vincent W. V. Jaddoe
Marjo-Riitta Jarvelin
Mark I. McCarthy
Craig E. Pennell
Chris Power
Nicholas J. Timpson
Elisabeth Widen
M. Arfan Ikram
Myriam Fornage
Albert V. Smith
Sudha Seshadri
Reinhold Schmidt
Stephanie Debette
Henri A. Vrooman
Sigurdur Sigurdsson
Stefan Ropele
Laura H. Coker
W. T. Longstreth
Wiro J. Niessen
Anita L. DeStefano
Alexa Beiser
Alex P. Zijdenbos
Maksim Struchalin
Clifford R. Jack
Mike A. Nalls
Rhoda Au
Albert Hofman
Haukur Gudnason
Aad van der Lugt
Tamara B. Harris
William M. Meeks
Meike W. Vernooij
Mark A. van Buchem
Diane Catellier
Vilmundur Gudnason
B. Gwen Windham
Philip A. Wolf
Cornelia M. van Duijn
Thomas H. Mosley
Helena Schmidt
Lenore J. Launer
Monique M. B. Breteler
Charles DeCarli
Institut für Biochemie und Biologie
Referiert
35935
2012
2012
eng
539
+
7
5
44
article
Nature Publ. Group
New York
Early Growth Genetics EGG Consorti, Cohorts Heart Aging Res Genomic Ep
1
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--
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Common variants at 6q22 and 17q21 are associated with intracranial volume
During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
Nature genetics
10.1038/ng.2245
1061-4036
wos:2011-2013
WOS:000303416300014
Ikram, MA (reprint author), Univ Med Ctr, Erasmus Med Ctr, Dept Epidemiol, Rotterdam, Netherlands., m.a.ikram@erasmusmc.nl; cdecarli@ucdavis.edu
US National Institute on Aging (NIA) [N01-AG-12100]; US NHLBI
[N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020,
N01-HC-55021, N01-HC-55022, R01-HL087641, R01-HL093029]; National Human
Genome Research Institute [U01-HG004402]; NIH [HHSN268200625226C]; NIH
Roadmap for Medical Research [UL1RR025005]; Austrian Science Fond (FWF)
[P20545-P05, P13180]; Framingham Heart Study of the NHLBI
[N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; Robert Dawson Evans
Endowment of the Department of Medicine at Boston University School of
Medicine and Boston Medical Center; National Institute of Neurological
Disorders and Stroke [NS17950]; NHLBI [HL093029, 5R01HL087679-02,
1RL1MH083268-01]; NIA [AG08122, AG16495, AG033193, AG033040, AG031287,
P30AG013846]; Netherlands Organisation of Scientific Research (NWO)
[175.010.2005.011, 911-03-012]; Research Institute for Diseases in the
Elderly [014-93-015]; Netherlands Genomics Initiative (NGI)- NWO
[050-060-810]; Erasmus Medical Center; Erasmus University Organization
for Health Research and Development (ZonMw); Research Institute for
Diseases in the Elderly (RIDE); Ministry of Education, Culture and
Science; Ministry for Health, Welfare and Sports; European Commission
(DG XII); Municipality of Rotterdam; NWO [918-46-615, 904-61-096,
904-61-133, 948-00-010]; Nederlandse Hartstichting [2009B102];
Internationaal Parkinson Fonds; Academy of Finland [104781, 120315,
1114194]; University Hospital Oulu, Biocenter, University of Oulu;
ENGAGE; UK MRC [G0500539, 74882]; Wellcome Trust [GR069224, 076467];
Biocentrum Helsinki; Erasmus Medical Center, Rotterdam; Erasmus
University Rotterdam; Netherlands Organization for Health Research and
Development (ZonMw) [21000074, 90700303, 916.10159]; Dutch Kidney
Foundation [C08.2251]; Children's Hospital of Philadelphia; Cotswold
Foundation; US NIH [1R01HD056465-01A1]; Healthway Western Australia;
National Health and Medical Research Council of Australia [572613];
Canadian Institutes of Health Research [MOP 82893]; University of
Bristol; [HEALTH-F4-2007-201413]
M. Arfan Ikram
Myriam Fornage
Albert V. Smith
Sudha Seshadri
Reinhold Schmidt
Stephanie Debette
Henri A. Vrooman
Sigurdur Sigurdsson
Stefan Ropele
H. Rob Taal
Dennis O. Mook-Kanamori
Laura H. Coker
W. T. Longstreth
Wiro J. Niessen
Anita L. DeStefano
Alexa Beiser
Alex P. Zijdenbos
Maksim Struchalin
Clifford R. Jack
Fernando Rivadeneira
Andre G. Uitterlinden
David S. Knopman
Anna-Liisa Hartikainen
Craig E. Pennell
Elisabeth Thiering
Eric A. P. Steegers
Hakon Hakonarson
Joachim Heinrich
Lyle J. Palmer
Marjo-Riitta Jarvelin
Mark I. McCarthy
Struan F. A. Grant
Beate St Pourcain
Nicholas J. Timpson
George Davey Smith
Ulla Sovio
Mike A. Nalls
Rhoda Au
Albert Hofman
Haukur Gudnason
Aad van der Lugt
Tamara B. Harris
William M. Meeks
Meike W. Vernooij
Mark A. van Buchem
Diane Catellier
Vincent W. V. Jaddoe
Vilmundur Gudnason
B. Gwen Windham
Philip A. Wolf
Cornelia M. van Duijn
Thomas H. Mosley
Helena Schmidt
Lenore J. Launer
Monique M. B. Breteler
Charles DeCarli
Linda S. Adair
Wei Ang
Mustafa Atalay
Toos vanBeijsterveldt
Nienke Bergen
Kelly Benke
Diane J. Berry
Lachlan Coin
Oliver S. P. Davis
Paul Elliott
Claudia Flexeder
Tim Frayling
Romy Gaillard
Maria Groen-Blokhuis
Liang-Kee Goh
Claire M. A. Haworth
Dexter Hadley
Johannes Hebebrand
Anke Hinney
Joel N. Hirschhorn
John W. Holloway
Claus Holst
Jouke Jan Hottenga
Momoko Horikoshi
Ville Huikari
Elina Hypponen
Tuomas O. Kilpelainen
Mirna Kirin
Matthew Kowgier
Hanna-Maaria Lakka
Leslie A. Lange
Debbie A. Lawlor
Terho Lehtimaki
Alex Lewin
Cecilia Lindgren
Virpi Lindi
Reedik Maggi
Julie Marsh
Christel Middeldorp
Iona Millwood
Jeffrey C. Murray
Michel Nivard
Ellen Aagaard Nohr
Ioanna Ntalla
Emily Oken
Kalliope Panoutsopoulou
Jennifer Pararajasingham
Alina Rodriguez
Rany M. Salem
Sylvain Sebert
Niina Siitonen
David P. Strachan
Yik-Ying Teo
Beatriz Valcarcel
Gonneke Willemsen
Eleftheria Zeggini
Dorret I. Boomsma
Cyrus Cooper
Matthew Gillman
Berthold Hocher
Timo A. Lakka
Karen L. Mohlke
George V. Dedoussis
Ken K. Ong
Ewan R. Pearson
Thomas S. Price
Chris Power
Olli T. Raitakari
Seang-Mei Saw
Andre Scherag
Olli Simell
Thorkild I. A. Sorensen
James F. Wilson
Institut für Ernährungswissenschaft
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