Rho-Associated Kinase Activity, Endothelial Function, and Cardiovascular Risk Factors

Abstract

Objective-Cardiovascular diseases are associated with chronic activation of Rho-associated kinases (ROCKs) and endothelial dysfunction. Both increased ROCK activity and endothelial dysfunction are thought to be closely associated with conventional cardiovascular risk factors. The purpose of this study was to determine the relationships between ROCK activity, endothelial function, and cardiovascular risk factors. Key Words: endothelial function Ⅲ risk factors Ⅲ Rho-associated kinases R ho-associated kinases (ROCKs), one of the first downstream targets of the small GTP-binding protein RhoA, play a pivotal role in the regulation of vascular smooth muscle contraction, endothelial function, and many cellular functions. 1-5 Several lines of evidence have shown that ROCK activity is enhanced in patients with angina pectoris, vasospastic angina, pulmonary hypertension, heart failure, and stroke. 6 -10 Increased ROCK activity may play a critical role in the pathogenesis and progression of several cardiovascular diseases.The vascular endothelium is involved in the release of various vasodilators, including nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor, as well as vasoconstrictors. 11,12 Nitric oxide plays an important role in the regulation of vascular tone, inhibition of platelet aggregation, and suppression of smooth muscle cell proliferation. Impaired endothelium-dependent vasodilation has been found in the forearm, coronary, and renal vasculature in patients with hypertension, 13-17 hypercholesterolemia, 18 diabetes mellitus, 19 and coronary artery diseases. 20,21 Endothelial dysfunction is the initial step in the pathogenesis of atherosclerosis, resulting in adverse cardiovascular and cerebrovascular outcomes. [22][23][24] Previous studies have shown that activation of the RhoA/ROCK pathway impairs nitric oxide bioavailability through downregulation of endothelial nitric oxide synthase mRNA stability and inhibition of endothelial nitric oxide synthase protein phosphorylation at Ser1177 via the Akt/ phosphatidylinositol 3-kinase pathway, suggesting that there is an interaction between ROCK activity and endothelial function. 25,26

Rho Kinases in Health and Disease: From Basic Science to Translational Research

“…In healthy subjects as well as those with cardiovascular risk factors but no established cardiovascular or (Soga et al, 2011). This later correlation thus suggests that leukocyte ROCK activity possibly predicts cardiovascular mortality and morbidity.…”

CKD Stimulates Muscle Protein Loss Via Rho-associated Protein Kinase 1 Activation

“…ROCK1 activity is regulated by small G proteins, such as RhoA, 33 to exert detrimental effects in pathophysiologic conditions, including obesity, cardiovascular diseases, renal fibrosis, and diabetes. [34][35][36] Recently, ROCK1 in mouse models of diabetic nephropathy has been identified as a mechanism causing mitochondrial fission and apoptosis in endothelial cells and podocytes. 32 There are other reports that ROCK1 triggered death-inducing signals in many cells but not in skeletal muscles.…”

Nitroglycerine-Induced Vasodilation for Assessment of Vascular Function

“…1 Recently, measurement of FMD in the brachial artery using high-resolution ultrasound, as an index of endothelium-dependent vasodilation, has been widely used as a method for assessing endothelial function. [2][3][4][7][8][9] Nitroglycerine-induced vasodilation, an index of endothelium-independent vasodilation, has been assessed as a control test to ensure that impaired FMD is not a result of underlying vascular smooth muscle dysfunction or alterations in vascular structure but truly a consequence of endothelial dysfunction. 16,17 However, it has been shown that nitroglycerine-induced vasodilation per se is impaired in adults with cardiovascular risk factors, or with coronary atherosclerosis and in children at risk for atherosclerosis.…”