@article{HechtFreisevonWebskyetal.2016,
  author    = {Hecht, Eva and Freise, Christian and von Websky, Karoline and Nasser, Hamoud and Kretzschmar, Nadja and Stawowy, Philipp and Hocher, Berthold and Querfeld, Uwe},
  title     = {The matrix metalloproteinases 2 and 9 initiate uraemic vascular calcifications},
  series = {Nephrology, dialysis, transplantation},
  volume    = {31},
  journal   = {Nephrology, dialysis, transplantation},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {0931-0509},
  doi       = {10.1093/ndt/gfv321},
  pages     = {789 -- 797},
  year      = {2016},
  abstract  = {The matrix metalloproteinases (MMP) MMP-2 and MMP-9 are physiological regulators of vascular remodelling. Their dysregulation could contribute to vascular calcification. We examined the role of the MMP-2 and MMP-9 in uraemic vascular calcification in vivo and in vitro. The impact of pharmacological MMP inhibition on the development of media calcifications was explored in an aggressive animal model of uraemic calcification. In addition, the selective effects of addition and inhibition, respectively, of MMP-2 and MMP-9 on calcium-/phosphate-induced calcifications were studied in a murine cell line of vascular smooth muscle cells (VSMCs). High-dose calcitriol treatment of uraemic rats given a high phosphate diet induced massive calcifications, apoptosis and increased gene expressions of MMP-2, MMP-9 and of osteogenic transcription factors and proteins in aortic VSMC. The MMP inhibitor doxycycline prevented the VSMC transdifferentiation to osteoblastic cells, suppressed transcription of mediators of matrix remodelling and almost completely blocked aortic calcifications while further increasing apoptosis. Similarly, specific inhibitors of either MMP-2 or -9, or of both gelatinases (Ro28-2653) and a selective knockdown of MMP-2/-9 mRNA expression blocked calcification of murine VSMC induced by calcification medium (CM). In contrast to MMP inhibition, recombinant MMP-2 or MMP-9 enhanced CM-induced calcifications and the secretion of gelatinases. These data indicate that both gelatinases provide essential signals for phenotypic VSMC conversion, matrix remodelling and the initiation of vascular calcification. Their inhibition seems a promising strategy in the prevention of vascular calcifications.},
  language  = {en}
}
@article{BirukovPolemitiJaegeretal.2022,
  author    = {Birukov, Anna and Polemiti, Elli and Jaeger, Susanne and Stefan, Norbert and Schulze, Matthias B.},
  title     = {Fetuin-A and risk of diabetes-related vascular complications},
  series = {Cardiovascular diabetology},
  volume    = {21},
  journal   = {Cardiovascular diabetology},
  number    = {1},
  publisher = {BMC},
  address   = {London},
  issn      = {1475-2840},
  doi       = {10.1186/s12933-021-01439-8},
  pages     = {11},
  year      = {2022},
  abstract  = {Background Fetuin-A is a hepatokine which has the capacity to prevent vascular calcification. Moreover, it is linked to the induction of metabolic dysfunction, insulin resistance and associated with increased risk of diabetes. It has not been clarified whether fetuin-A associates with risk of vascular, specifically microvascular, complications in patients with diabetes. We aimed to investigate whether pre-diagnostic plasma fetuin-A is associated with risk of complications once diabetes develops. Methods Participants with incident type 2 diabetes and free of micro- and macrovascular disease from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (n = 587) were followed for microvascular and macrovascular complications (n = 203 and n = 60, respectively, median follow-up: 13 years). Plasma fetuin-A was measured approximately 4 years prior to diabetes diagnosis. Prospective associations between baseline fetuin-A and risk of complications were assessed with Cox regression. Results In multivariable models, fetuin-A was linearly inversely associated with incident total and microvascular complications, hazard ratio (HR, 95\% CI) per standard deviation (SD) increase: 0.86 (0.74; 0.99) for total, 0.84 (0.71; 0.98) for microvascular and 0.92 (0.68; 1.24) for macrovascular complications. After additional adjustment for cardiometabolic plasma biomarkers, including triglycerides and high-density lipoprotein, the associations were slightly attenuated: 0.88 (0.75; 1.02) for total, 0.85 (0.72; 1.01) for microvascular and 0.95 (0.67; 1.34) for macrovascular complications. No interaction by sex could be observed (p > 0.10 for all endpoints). Conclusions Our data show that lower plasma fetuin-A levels measured prior to the diagnosis of diabetes may be etiologically implicated in the development of diabetes-associated microvascular disease.},
  language  = {en}
}
@article{ZebgerGongMuellerDierckeetal.2011,
  author    = {Zebger-Gong, Hong and Mueller, Dominik and Diercke, Michaela and Haffner, Dieter and Hocher, Berthold and Verberckmoes, Steven and Schmidt, Sven and D'Haese, Patrick C. and Querfeld, Uwe},
  title     = {1,25-Dihydroxyvitamin D-3-induced aortic calcifications in experimental uremia: up-regulation of osteoblast markers, calcium-transporting proteins and osterix},
  series = {Journal of hypertension},
  volume    = {29},
  journal   = {Journal of hypertension},
  number    = {2},
  publisher = {Lippincott Williams \& Wilkins},
  address   = {Philadelphia},
  issn      = {0263-6352},
  doi       = {10.1097/HJH.0b013e328340aa30},
  pages     = {339 -- 348},
  year      = {2011},
  abstract  = {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.},
  language  = {en}
}