2015 ATVB Plenary Lecture

Abstract

Abstract-Rho-kinase (ROCKs) is an important downstream effector of the small GTP-binding protein Ras homolog gene family member A. There are 2 isoforms of ROCK, ROCK1 and ROCK2, and they have different functions in several vascular components. The Ras homolog gene family member A/ROCK pathway plays an important role in various fundamental cellular functions, including contraction, motility, proliferation, and apoptosis, whereas its excessive activity is involved in the pathogenesis of cardiovascular diseases. For the past 20 years, a series of translational research studies have demonstrated the important roles of ROCK in the pathogenesis of cardiovascular diseases. At the molecular and cellular levels, ROCK upregulates several molecules related to inflammation, thrombosis, and fibrosis. In animal experiments, ROCK plays an important role in the pathogenesis of vasospasm, arteriosclerosis, hypertension, pulmonary hypertension, and heart failure. Finally, at the human level, ROCK is substantially involved in the pathogenesis of coronary vasospasm, angina pectoris, hypertension, pulmonary hypertension, and heart failure. Furthermore, ROCK activity in circulating leukocytes is a useful biomarker for the assessment of disease severity and therapeutic responses in vasospastic angina, heart failure, and pulmonary hypertension. In addition to fasudil, many other ROCK inhibitors are currently under development for various indications. Thus, the ROCK pathway is an important novel therapeutic target in cardiovascular medicine. ). [20][21][22][23] Both endothelial NO production and NO-mediated signaling in VSMC are targets and effectors of the RhoA/ROCK pathway. 1,24,25 In EC, the RhoA/ROCK pathway negatively regulates NO production, although in VSMC, the pathway enhances MLC phosphorylation through inhibition of MYPT-1 of MLCP and promotes VSMC contraction ( Figure 1). 26ROCK is a serine/threonine kinase, which is encoded by 2 different genes. In humans, ROCK1 (ROCKβ) and ROCK2 (ROCKα) genes are located separately on chromosome 18 and 2, respectively. 27,28 ROCK consists of 3 major domains, including a kinase domain, a coiled-coil domain that include Rhobinding domain and a putative pleckstrin homology domain ( Figure 3). 4 ROCK activity is enhanced by binding of GTPbound active form of RhoA.28 Several ROCK substrates have been identified 27 and phosphorylation of ROCK-mediated substrate causes actin filament formation, organization, and cytoskeleton rearrangement (Figure 1). 29 Nowadays, many ROCK inhibitors, such as fasudil 30 and Y-27632, 31 have been developed and they inhibit ROCK activity in a competitive manner with ATP at the Rho-binding site. 32 Among them, hydroxyfasudil, a major active metabolite of fasudil, exerts a more specific inhibitory effect on ROCK. 33,34 Roles of ROCK in ECThe RhoA/ROCK pathway is critically involved in actin dynamics. 35 Cyclic strain stimulates RhoA activation and enhances cell contractility. Mechanical activation of the RhoA/ROCK system makes cells more sensitive to external stimuli...

RhoA/Rho-Kinase in the Cardiovascular System

“…2,3,14,125,126 The beneficial effects of long-term inhibition of Rho-kinase for the treatment of cardiovascular disease have been demonstrated in various animal models, such as coronary artery spasm, arteriosclerosis, restenosis, ischemia/reperfusion injury, hypertension, PH, stroke, and cardiac hypertrophy/heart failure. 2,14,112,125 Gene transfer of dominant-negative Rho-kinase reduced neointimal formation of the coronary artery in pigs.…”

“…109,123 Indeed, Rho-kinase is an important therapeutic target in cardiovascular diseases. 2,3,14 On the basis of role of extracellular CyPA, we think that it is logical to consider that agents that prevent CyPA receptor binding and reduce circulating CyPA may have therapeutic potentials. Blocking the vicious cycle that increases ROS production through autocrine/paracrine CyPA signaling pathway mediated by Rho-kinase could be a novel therapeutic tool for controlling cardiovascular diseases (Figure 4).…”

“…3 ROS are involved in the pathogenesis of neointima formation, in part, by promoting VSMC growth and stimulating proinflammatory events. 102,182 Arteriosclerosis is a slowly progressing process of inflammation of the arterial wall that involves the intima, media, and adventitia.…”

“…ECs release vasoactive factors, such as prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing (EDH) factors, which participate in the regulation of vascular tone and resistance. [1][2][3] Twenty years ago, Rho-kinases (Rho-kinase α/ROKα/ROCK2 and Rho-kinase β/ROKβ/ROCK1) were identified as the effectors of the small GTP-binding protein, RhoA, independently by 3 research groups. [4][5][6] Hereafter, both Rho-kinase α/ROKα/ROCK2 and Rho-kinase β/ROKβ/ ROCK1 are collectively referred to as Rho-kinase.…”

Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice

“…41 Indeed, activation of eNOS catalyzes the production of NO, which is a crucial molecule for the maintenance of endothelial function and vascular homeostasis. 42 Indeed, Afolayan et al 43 demonstrated that phosphorylation of APMK and mitochondrial biogenesis are downregulated in fetal lambs with persistent PH of the newborn. In addition, eNOS phosphorylation in PAEC increased superoxide dismutase-2 levels and decreased the mitochondrial superoxide levels in this animal model of persistent PH of the newborn.…”