The potent vasodilator action of cyclic GMP-dependent protein kinase (cGK) involves decreasing the Ca

Abstract-Rho kinases (ROCKs) are the first and the best-characterized effectors of the small G-protein RhoA. In addition to their effect on actin organization, or through this effect, ROCKs have been found to regulate a wide range of fundamental cell functions such as contraction, motility, proliferation, and apoptosis. Abnormal activation of the RhoA/ROCK pathway has been observed in major cardiovascular disorders such as atherosclerosis, restenosis, hypertension, pulmonary hypertension, and cardiac hypertrophy. This review, based on recent molecular, cellular, and animal studies, focuses on the current understanding of ROCK signaling and its roles in cardiovascular physiology and pathophysiology. (Circ Res. 2006;98:322-334.)Key Words: Rho kinase Ⅲ cardiovascular diseases Ⅲ Rho-GTP-binding proteins Ⅲ signal transduction R hoA is one of the best-known members of the Rho protein family that, in addition to its effect on actin organization or through this effect, regulate a wide range of fundamental cell functions such as contraction, motility, proliferation, and apoptosis. 1 RhoA acts as a molecular switch that cycles between an inactive GDP-bound and an active GTP-bound conformation interacting with downstream targets (effectors) to elicit cellular responses. Rho kinases (ROCKs) are the first and the bestcharacterized RhoA effectors. However, ROCKs can be considered more generally as Rho effectors because they also bind other Rho proteins such as RhoB and RhoC. 2 Since their discovery in 1996, ROCKs have been extensively studied, leading to the publication of Ͼ1300 articles, many of which focus on ROCK functions in the cardiovascular system. The interest for ROCKs in the heart and vessels has been further reinforced by the observation that the beneficial cardiovascular effects of statins result, at least in part, from the inhibition of ROCKs. 3 Indeed, by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins reduce cholesterol synthesis but also prevent the formation of geranylgeranylpyrophosphate required for membrane translocation and activation of RhoA, the main upstream activator of ROCKs. In this review, we describe the current understanding of ROCK signaling and its roles in cardiovascular physiology and pathophysiology.

Hypertension is one of the most frequent pathologies in the industrialized world. Although recognized to be dependent on a combination of genetic and environmental factors, its molecular basis remains elusive. Increased activity of the monomeric G protein RhoA in arteries is a common feature of hypertension. However, how RhoA is activated and whether it has a causative role in hypertension remains unclear. Here we provide evidence that Arhgef1 is the RhoA guanine exchange factor specifically responsible for angiotensin II-induced activation of RhoA signaling in arterial smooth muscle cells. We found that angiotensin II activates Arhgef1 through a previously undescribed mechanism in which Jak2 phosphorylates Tyr738 of Arhgef1. Arhgef1 inactivation in smooth muscle induced resistance to angiotensin II-dependent hypertension in mice, but did not affect normal blood pressure regulation. Our results show that control of RhoA signaling through Arhgef1 is central to the development of angiotensin II-dependent hypertension and identify Arhgef1 as a potential target for the treatment of hypertension.