Rho kinase inhibition activates the homologous angiotensin-converting enzyme-angiotensin-(1-9) axis in experimental hypertension

Background Angiotensin II (Ang II) levels depend on renin, angiotensin-converting enzyme (ACE), and on the homologous angiotensin-converting enzyme (ACE2). Increased ACE and Ang II levels are associated with higher Rho kinase activity. However, the relationship between Rho kinase activation and ACE2 in hypertension is unknown. Objective The role of the Rho kinase signaling pathway in both enzymatic activity and aortic gene expression of ACE2 in deoxycorticosterone acetate (DOCA) hypertensive rats was assessed in the present study. Methods and results Compared with sham animals, Rho kinase activity was higher by 400% (P < 0.05) in the aortic wall of the DOCA hypertensive rats. In addition to blood pressure reduction, the specific Rho kinase inhibitor fasudil reduced aortic Rho kinase activity to levels observed in the sham control group and increased ACE2 enzymatic activity (by 83% in plasma and by 52% in the aortic wall, P < 0.05), ACE2, and endothelial nitric oxide synthase (eNOS) aortic mRNA levels (by 340 and 40%, respectively, P < 0.05) with respect to the untreated hypertensive DOCA rats. Fasudil also increased significantly plasma levels of Ang-(1-9) in normotensive and in the hypertensive rats. Aortic mRNA and protein levels of transforming growth factor-beta(1) (TGF-beta(1)), plasminogen activator inhibitor 1 (PAI-1), and monocyte chemoattractant protein 1 (MCP-1) were significantly (P < 0.05) higher in the untreated DOCA rats and were normalized by fasudil administration. Conclusion In experimental hypertension, Rho-associated, coiled-coil containing protein kinase (ROCK) inhibition reduces blood pressure and increases ACE2 levels and activity. At the same time, ROCK inhibition reduces angiotensin II and increases Ang-(1-9) plasma levels. Fasudil also increases vascular eNOS mRNA levels and reduces aortic overexpression of the remodeling promotion proteins TGF-beta(1), PAI-1, and MCP-1. This effect might additionally contribute to the antihypertensive and antiremodeling effects of ROCK inhibition in hypertension. J Hypertens 29:706-715 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.