TY  - JOUR
A1  - Satwiko, Muhammad Gahan
A1  - Ikeda, Koji
A1  - Nakayama, Kazuhiko
A1  - Yagi, Keiko
A1  - Hocher, Berthold
A1  - Hirata, Ken-Ichi
A1  - Emoto, Noriaki
T1  - Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension
JF  - Biochemical and biophysical research communications
N2  - Pulmonary arterial hypertension (PAH) is a fatal disease that eventually results in right heart failure and death. Current pharmacologic therapies for PAH are limited, and there are no drugs that could completely cure PAH. Enhanced activity of endothelin system has been implicated in PAH severity and endothelin receptor antagonists have been used clinically to treat PAH. However, there is limited experimental evidence on the direct role of enhanced endothelin system activity in PAL-I. Here, we investigated the correlation between endothelin-1 (ET-1) and PAH using ET-1 transgenic (ETTG) mice. Exposure to chronic hypoxia increased right ventricular pressure and pulmonary arterial wall thickness in ETTG mice compared to those in wild type mice. Of note, ETTG mice exhibited modest but significant increase in right ventricular pressure and vessel wall thickness relative to wild type mice even under normoxic conditions. To induce severe PAH, we administered SU5416, a vascular endothelial growth factor receptor inhibitor, combined with exposure to chronic hypoxia. Treatment with SU5416 modestly aggravated hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial vessel wall thickening in ETTG mice in association with increased interleukin-6 expression in blood vessels. However, there was no sign of obliterative endothelial cell proliferation and plexiform lesion formation in the lungs. These results demonstrated that enhanced endothelin system activity could be a causative factor in the development of PAH and provided rationale for the inhibition of endothelin system to treat PAH. (C) 2015 Elsevier Inc. All rights reserved.
KW  - Pulmonary arterial hypertension
KW  - Endothelin
KW  - Hypoxia
KW  - SU5416
Y1  - 2015
U6  - https://doi.org/10.1016/j.bbrc.2015.08.002
SN  - 0006-291X
SN  - 1090-2104
VL  - 465
IS  - 3
SP  - 356
EP  - 362
PB  - Elsevier
CY  - San Diego
ER  -