靶向Rho通路的抗高血压治疗策略研究进展

Targeting Rho pathway for anti-hypertensive treatment:research advances

在过去几十年中,高血压的患病率呈逐年上升趋势。它不但增加左心室肥厚、心绞痛、心肌梗死和心力衰竭等心血管疾病的患病风险,还可能导致卒中(中风)、肾衰竭等相关后遗症。尽管目前有多种降压方案可供选择,但经过药物治疗后,只有半数患者可有效控制血压,这意味着需要进一步了解潜在的致病因素并寻求更有效的治疗方法。然而血压稳态非常复杂,涉及多个系统的综合控制,其中平滑肌收缩力和动脉阻力是重要因素。来自临床前动物模型和全基因组关联研究的有力证据表明,平滑肌收缩和血压稳态受小分子GTP酶RhoA及其下游靶点Rho激酶控制。本文总结了平滑肌细胞中对RhoA活性进行严格控制的信号通路及调节器的相关进展,并讨论了当前针对这些RhoA通路成分的高血压治疗策略。还讨论了RhoA通路中已知的等位基因变异,并介绍了这些遗传多态性对高血压遗传风险的影响及其临床表现。

In the past few decades,the prevalence of hypertension has steadily increased. Hypertention is known as a silent killer,which not only increases the risk of cardiovascular disease,but also can lead to stroke,heart attack,kidney failure and related sequelae. Although there are currently a variety of anti-hypertensive therapies available,only half of the patients have effective blood pressure(BP)control after medication treatment,which means a better understanding of potential pathogenic factors is needed for seeking more effective treatments. However,BP homeostasis is very complex and involves comprehensive control of multiple systems,in which smooth muscle contractility and arterial resistance are important factors. Strong evidence from pre-clinical animal model and genome-wide association studies have suggested that the smooth muscle contraction and BP homeostasis are controlled by the small molecule GTPase RhoA and its downstream target,Rho-associated coiled coil domain containing protein kineses(ROCK). In this review,we summarize research progress in the pathways and regulators that control RhoA activity in smooth muscle cells,and discuss current treatment strategies targeting these RhoA pathway components for treatment of hypertension. We also discuss known allelic variations in the RhoA pathway and introduce the effect of the polymorphism on the genetic risk of hypertension and its clinical manifestations.