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CPI-17-mediated contraction of vascular smooth muscle is essential for the development of hypertension in obese mice

Author:
Sun, Jie, Tao, Tao, Zhao, Wei, Wei, Lisha, She, Fan, Wang, Pei, Li, Yeqiong, Zheng, Yanyan, Chen, Xin, Wang, Wei, Qiao, Yanning, Zhang, Xue-Na, Zhu, Min-Sheng
Source:
Journal of genetics and genomics 2019 v.46 no.3 pp. 109-118
ISSN:
1673-8527
Subject:
G-protein coupled receptors, agonists, animal disease models, blood pressure, calcium, high fat diet, hypertension, mice, muscles, mutants, obesity, protein kinase C, signal transduction, smooth muscle
Abstract:
Several factors have been implicated in obesity-related hypertension, but the genesis of the hypertension is largely unknown. In this study, we found a significantly upregulated expression of CPI-17 (C-kinase-potentiated protein phosphatase 1 inhibitor of 17 kDa) and protein kinase C (PKC) isoforms in the vascular smooth muscles of high-fat diet (HFD)-fed obese mice. The obese wild-type mice showed a significant elevation of blood pressure and enhanced calcium-sensitized contraction of vascular smooth muscles. However, the obese CPI-17-deficient mice showed a normotensive blood pressure, and the calcium-sensitized contraction was consistently reduced. In addition, the mutant muscle displayed an abolished responsive force to a PKC activator and a 30%–50% reduction in both the initial peak force and sustained force in response to various G protein-coupled receptor (GPCR) agonists. Our observations showed that CPI-17-mediated calcium sensitization is mediated through a GPCR/PKC/CPI-17/MLCP/RLC signaling pathway. We therefore propose that the upregulation of CPI-17-mediated calcium-sensitized vasocontraction by obesity contributes to the development of obesity-related hypertension.
Agid:
6342523