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P-3
Cardiovascular Disease: Emerging Science and Therapeutics
ROCK as a Novel Biomarker and Therapeutic Target for Cardiovascular Disease
James K. Liao, M.D.
University of Chicago, Chicago, IL, USA

 Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are widely used to lower serum cholesterol levels in the primary and secondary prevention of cardiovascular disease. Recent experimental and clinical evidence suggest that the beneficial effects of statins may extend beyond their cholesterol lowering effects, to include so-called pleiotropic effects. These cholesterol-independent effects include improving endothelial function, attenuating vascular and myocardial remodeling, inhibiting vascular inflammation and oxidation, and stabilizing atherosclerotic plaques. The mechanism underlying some of these pleiotropic effects is the inhibition of isoprenoid synthesis by statins, which leads to the inhibition of intracellular signaling molecules such as Rho, Rac and Cdc42. In particular, inhibition of Rho and one of its downstream targets, Rho kinase (ROCK), may be a predominant mechanism contributing to the pleiotropic effects of statins. Indeed, one of the beneficial effects of statin therapy could be due to inhibitory effects on ROCK.
  Because ROCKs mediate various important cellular functions such as cell shape, motility, secretion, proliferation, and gene expression, it is likely that this pathway will intersect with other signaling pathways known to contribute to cardiovascular disease. Indeed, ROCKs have already been implicated in the regulation of vascular tone, proliferation, inflammation, and oxidative stress. While increased leukocyte ROCK activity is associated with endothelial dysfunction, cerebral ischemia, coronary vasospasms, metabolic syndrome, and heart failure, the inhibition of ROCK by statins or selective ROCK inhibitors leads to upregulation of endothelial nitric oxide synthase (eNOS), decreased vascular inflammation, and reduced atherosclerotic plaque formation. However, it is not entirely clear how ROCKs are regulated, what some of their downstream targets are, and whether ROCK1 and ROCK2 mediate different cellular functions. Clinically, inhibition of ROCK pathway is believed to contribute to some of the cardiovascular benefits of statin therapy that are independent of lipid lowering, i.e., pleiotropic effects. To what extent ROCK activity is inhibited in patients on statin therapy is not known, but may have important clinical implications. Indeed, several pharmaceutical companies are already actively engaged in the development of ROCK inhibitors as the next generation of therapeutic agents for cardiovascular disease since evidence from animal studies suggests the potential involvement of ROCK in hypertension and atherosclerosis. Thus, findings from bench to bedside support ROCK as a novel biomarker and therapeutic target for cardiovascular disease.