Iizuka Kenji, Machida Takuji, Kawaguchi Hideaki, Hirafuji Masahiko
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan.
Cardiovasc Drugs Ther. 2008 Oct;22(5):383-90. doi: 10.1007/s10557-008-6118-7. Epub 2008 Aug 5.
Hypertension is a major risk factor for atherosclerosis, and elevated pressure (i.e., mechanical pressure stresses) has been known to modulate vascular remodeling, possibly by affecting the tissue renin-angiotensin system.
In the present study we applied pulsatile pressure to human aortic smooth muscle cells (HASMCs) and investigated whether mechanical pressure stress affects cell proliferation and/or the angiotensin-converting enzyme (ACE), and we tested whether the administration of an angiotensin II (AII) receptor blocker has a favorable effect.
Three hours of pulsatile atmospheric pressure resulted in an approximately 8% increase in cell proliferation of human aortic smooth muscle cells. The cell surface ACE level, enzyme activity and mRNA expression were all elevated (37%, 110% and 17%, respectively) under pressurized conditions, and co-administration of AII reduced all these values. The reductions in these three parameters resulting from the administration of AII were all abolished by AII receptor blocker co-administration and values were increased (11%, 62% and 12%, respectively) under pressurized conditions. Pulsatile atmospheric pressure increased the amount of phosphorylated extracellular signal-regulated kinase (ERK) by approximately 54% in HASMCs. The administration of PD98059 (10 microM) resulted in a decrease in phosphorylated ERK and ACE activity in HASMCs compared to those of the pressurized control.
From these observations, we conclude that pulsatile mechanical pressure is one of the mediators of ACE production in vascular smooth muscle cells and that AII receptor blocking may prevent negative feedback. The present findings may provide a potential therapeutical target beyond lowering blood pressure in hypertensive patients.
高血压是动脉粥样硬化的主要危险因素，已知压力升高（即机械压力应激）可能通过影响组织肾素 - 血管紧张素系统来调节血管重塑。
在本研究中，我们对人主动脉平滑肌细胞（HASMCs）施加脉动压力，研究机械压力应激是否影响细胞增殖和/或血管紧张素转换酶（ACE），并测试给予血管紧张素II（AII）受体阻滞剂是否具有有益作用。
三小时的脉动大气压导致人主动脉平滑肌细胞的细胞增殖增加约8％。在加压条件下，细胞表面ACE水平、酶活性和mRNA表达均升高（分别为37％、110％和17％），同时给予AII可降低所有这些值。给予AII导致的这三个参数的降低在同时给予AII受体阻滞剂后均被消除，并且在加压条件下这些值增加（分别为11％、62％和12％）。脉动大气压使HASMCs中磷酸化细胞外信号调节激酶（ERK）的量增加约54％。与加压对照组相比，给予PD98059（10 microM）导致HASMCs中磷酸化ERK和ACE活性降低。
从这些观察结果中，我们得出结论，脉动机械压力是血管平滑肌细胞中ACE产生的介质之一，并且AII受体阻断可能会阻止负反馈。本研究结果可能为高血压患者提供除降低血压之外的潜在治疗靶点。
