Rho-associated coiled-coil-forming kinases (ROCKs): potential targets for the treatment of atherosclerosis and vascular disease

Abstract

The Rho/Rho-associated coiled-coil forming kinases (ROCKs) are important regulators of the actin cytoskeleton. Because changes in the actin cytoskeleton underlie vascular contractility and remodeling, inflammatory cell recruitment, and cellular proliferation, it is likely that the Rho/ ROCK pathway will play a central role in mediating vascular function. Indeed, increased ROCK activity is observed in cerebral and coronary vasospasm, hypertension, vascular inflammation, arteriosclerosis, and atherosclerosis. Recent experimental and clinical studies suggest that inhibition of ROCK could be a promising target for the treatment of cardiovascular disease. For example, inhibition of ROCK might be the underlying mechanism by which statins or HMG-CoA reductase inhibitors exert their therapeutic benefits beyond cholesterol reduction. In this review, we provide a current understanding of the critical role of RhoA/ROCK pathway in the regulation of vascular function and discuss its therapeutic potential in the treatment of atherosclerosis and vascular disease.

Differential Effects of Atorvastatin and Pitavastatin on Inflammation, Insulin Resistance, and the Carotid Intima-Media Thickness in Patients with Dyslipidemia

“…Statins inhibit the HMG-CoA reductase activity and decrease the isoprenylation of intracellular signaling molecules, including Rho 10, 36,37) . Rho kinases (ROCKs) are protein serine/threonine kinases of approximately 160 kDa that act as downstream effectors of the small glutamyltranspeptidase (GTPase) Rho.…”

“…Statins prevent the membrane targeting of Rho and its subsequent activation of ROCKs by inhibiting mevalonate synthesis. At clinically relevant concentrations, statins have been shown to inhibit the isoprenylation of Rho and activity of ROCK 36,37) . The Rho/ROCK pathway is involved in the onset of hypertension and cardiac hypertrophy and progression of atherosclerosis 36,37) .…”

Rock the Rock of Atherosclerosis

“…Accumulating experimental and clinical evidence indicates that the Rho/ROCK signaling pathway is critically involved in the pathogenesis of atherosclerotic diseases and that inhibition of ROCK by ROCK inhibitors (such as fasudil, Y-27632 and lipid-lowering statins) are beneficial [6,8,27]. In terms of the fact that ROCK1 and ROCK2 mediate different cellular processes, more efforts will be made to develop morespecific and more-potent ROCK inhibitors.…”

“…Indeed, ROCK is up-regulated by inflammatory stimuli, such as angiotensin II and interleukin-1β, lipopolysaccharide (LPS) and oxLDL [3,5]. More recently, there are several excellent reviews [5][6][7][8] addressing the role of Rho/ROCK pathway in mediating multiple cellular functions and the use of ROCK inhibitors in cardiovascular diseases. ROCK has been shown to be up-regulated in inflammatory atherosclerotic lesions and administration of a RhoA/ROCK inhibitor (Y-27632, 30 mg/kg/d, 9 weeks) significantly decreased early atherosclerotic lesion formation [9].…”

Rho‐kinase Gene Polymorphisms in Related Disease States

“…ROCK signaling has been implicated in a wide range of fundamental cellular functions including cell morphology, contraction, adhesion, motility, migration, proliferation, diferentiation, invasion, metastasis, and apoptosis [1,2]. ROCK can also regulate macrophage phagocytic activity and endothelial cell permeability, and it is known to play a role in inlammatory mechanisms and endothelial dysfunction [7,8].…”