Model Animal Research Center and MOE Key Laboratory of Model Animal and Disease Study, Nanjing University, Nanjing, 210061, China.
Key Laboratory of MOE for Modern Teaching Technology, Shaanxi Normal University, Xi'an, 710062, China.
J Genet Genomics. 2019 Mar 20;46(3):109-118. doi: 10.1016/j.jgg.2019.02.005. Epub 2019 Mar 15.
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.
多种因素与肥胖相关高血压有关，但高血压的发生机制在很大程度上尚不清楚。在这项研究中，我们发现高脂饮食喂养的肥胖小鼠血管平滑肌中 CPI-17（蛋白激酶 C 增强的蛋白磷酸酶 1 抑制剂 17kDa）和蛋白激酶 C 同工型的表达显著上调。肥胖野生型小鼠表现出显著的血压升高和血管平滑肌钙敏收缩增强。然而，肥胖的 CPI-17 缺陷型小鼠血压正常，钙敏收缩持续减少。此外，突变肌对蛋白激酶 C 激活剂的反应力丧失，对各种 G 蛋白偶联受体 (GPCR) 激动剂的初始峰值力和持续力分别减少 30%至 50%。我们的观察表明，CPI-17 介导的钙敏化是通过 GPCR/PKC/CPI-17/MLCP/RLC 信号通路介导的。因此，我们提出肥胖引起的 CPI-17 介导的钙敏化血管收缩增加导致肥胖相关高血压的发生。
