Rho Kinases in Cardiovascular Physiology and Pathophysiology

Abstract

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.

Rho kinase in the regulation of cell death and survival

“…The consensus sequence of ROCK substrates is R/K-X-S/T or R/K-X-X-S/T (R, arginine; K, lysine; S, serine; T, threonine) [4,37,41,61,83]. More than 20 ROCK substrates have been identified (reviewed in refs [51,78,113]). …”

“…During the last decade, the Rho/ROCK signaling pathway has attracted much attention in various research fields, and more than 2,000 articles have been published; many of which focus on ROCK function in the cardiovascular system, central nervous system, cancers and embryonic development. Several excellent recent reviews have covered large aspects [11,33,51,78,94,97,113,123]. The up to date progress in the translational research has demonstrated that ROCK is an important therapeutic target for the treatment of various cardiovascular diseases and neurological disorders, cancers, etc.…”

Roles of transglutaminases in cardiac and vascular diseases

“…RhoA, a small GTPase, is a member of the Ras superfamily and has roles in cell adhesion, migration, cytoskeletal organization as well as a variety of other cellular functions (139). TG2 can activate RhoA by two mechanisms.…”

Activation of Rho Kinase by TNF-α Is Required for JNK Activation in Human Pulmonary Microvascular Endothelial Cells

“…A major substrate of Rho kinase is myosin phosphatase target subunit (MYPT-1), and phosphorylation of MYPT-1 by Rho kinase leads to inhibition of myosin phosphatase activity, resulting in increased myosin L chain phosphorylation and actin-myosin-mediated contractility (18). Rho kinase activation can also be induced through Rho-independent mechanisms.…”

“…Rho kinase activation can also be induced through Rho-independent mechanisms. Binding of lipid messengers, including arachidonic acid or sphingosine phosphorylcholine, to Rho kinase or proteolytic cleavage of Rho kinase by caspase 3 or granzyme B can efficiently activate Rho kinase independent of Rho (18).…”