Long-Term Inhibition of Rho-kinase Ameliorates Hypoxia-Induced Pulmonary Hypertension in Mice

Abstract

Pulmonary hypertension (PH) is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells, and migration of inflammatory cells for which no satisfactory treatment has yet been developed. It has been recently demonstrated that Rho-kinase, an effector of the small GTPase Rho, is involved in the pathogenesis of arteriosclerosis and that long-term inhibition of Rho-kinase markedly ameliorates monocrotaline-induced PH in rats. However, it remains to be examined whether direct inhibition of Rho-kinase also ameliorates PH with a different etiology and whether endothelial nitric oxide synthase (eNOS) is involved in the beneficial effects of Rho-kinase inhibition. This study was designed to address those 2 important issues in a hypoxia-induced PH model using wild-type (WT) and eNOS-deficient (eNOS) mice. Long-term blockade of Rho-kinase with fasudil (100 mg/kg/d) for 3 weeks markedly improved PH and right ventricular hypertrophy in WT mice with a lesser but significant inhibition noted in eNOS mice. Fasudil upregulated eNOS with increased Akt phosphorylation in WT but not in eNOS mice. These results suggest that long-term inhibition of Rho-kinase also ameliorates hypoxia-induced PH in mice, for which eNOS activation may partially be involved.

Evidence for Rho-Kinase Activation in Patients With Pulmonary Arterial Hypertension

“…These findings are consistent with our previous studies with MCT-induced PH in rats and hypoxia-induced PH in mice, 10,11 and previous clinical studies of patients with PAH. [23][24][25][26][27][28][29][30][31][32][33][34][35] Furthermore, we were able to demonstrate that inhibition of Rho-kinase abolished VSMC hypercontraction of pulmonary arteries from IPAH patients.…”

Pulmonary Vascular and Ventricular Dysfunction in the Susceptible Patient (2015 Grover Conference Series)

“…75 ROCK may represent a node of convergence with channels/ transporters involved in remodeling, as ROCK activation opens Ca 2+ channels 51,76 and stimulates the activity of 77 and is activated by 73 NHE1. Chronic treatment with ROCK inhibitors reduced neovascularization and remodeling in HPH models; 34,78,79 ROCK activation is necessary for migration and proliferation in a variety of vascular cell types, including PASMCs; [80][81][82][83] and the upstream activators of ROCK, RhoA and RhoB, mediate cytoskeletal rearrangement in PASMCs, 84 a process necessary for cell movement, a key component of both migratory and proliferative processes.…”

Hypoxia Selectively Activates the CREB Family of Transcription Factors in the In Vivo Lung

“…Moreover, cor pulmonale is an independent predictor of increased mortality, suggesting that pulmonary hypertension contributes directly to reduced survival (1,2). The increased pulmonary vascular resistance underlying chronic hypoxic pulmonary hypertension is accompanied by characteristic changes in the blood vessels, which include remodeling and thickening of the walls of precapillary vessels and sustained vasoconstriction (3)(4)(5)(6)(7)(8). These long-term structural and functional changes in the pulmonary vessels in response to hypoxia are unique to this circulation, and are not observed in the vasculature of other organs of the body.…”