Rho kinase activation in circulating leukocytes is related to hypertensive myocardial remodeling.

Abstract

Rho-kinase has relevant functions in blood pressure modulation and cardiovascular remodeling. Rho-kinase activity is determined in circulating leukocytes measuring phosphorylation of its target myosin phosphatase target subunit 1 (MYPT1), but its relationship with Rho-kinase activity in the myocardium and in vasculature in hypertension has not been evaluated.The aim was to determine the degree of association between Rho-kinase cascade activation in circulating leukocytes with cardiac and aortic Rho-kinase pathway activation in a model of hypertension and to analyze it with a cause-effect perspective.Hypertensive deoxycorticosterone (DOCA)-salt rats received the Rho-kinase antagonist fasudil (DOCA-Fas, 100 mg/kg/day, 3 weeks). Results were compared with an untreated DOCA-salt and a sham group.Rho-kinase inhibition reduced significantly blood pressure, cardiac hypertrophy, myocardial collagen and macrophage infiltration, but not aortic wall hypertrophy. Fasudil decreased significantly Rho-kinase activity in peripheral blood mononucleated cells (PBMC), myocardium and aortic wall to similar levels as in the sham group. A significant correlation was found between PBMC Rho-kinase activity and cardiac remodeling, specifically with hypertrophy (r = 0.51, P≤0.01), myocardial collagen (r = 0.40, P≤0.05) and ED1 immunostaining (r = 0.48, P≤0.01). In the untreated hypertensive group, increased levels (P<0.05) of the proinflammatory molecules p65 NF-κB, vascular cell adhesion molecule 1 and interleukin-6 antibody in the myocardium, aortic wall and PBMC were observed and were reduced with fasudil (P<0.05).In conclusion, in this hypertension model, Rho-kinase and its pathway activation determined in circulating leukocytes reflect the activation of this pathway in the myocardium and in the aortic wall and are significantly related to myocardial remodeling (hypertrophy, fibrosis and inflammation).

• Authors: Maria P Ocaranza, Camila Fierro, Jorge E Jalil, Jackeline Moya, Leticia Gonzalez, Cristián Molina, Cristián Mancilla
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 132 Issue 16 Pg. 1837-1853 (08 31 2018) ISSN: 1470-8736 [Electronic] England
• PMID: 30065083 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• Protein Kinase Inhibitors
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• rho-Associated Kinases
• fasudil

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, pharmacology)
• Animals
• Atrial Remodeling (drug effects, physiology)
• Blood Pressure (drug effects, physiology)
• Cardiomegaly (physiopathology, prevention & control)
• Cells, Cultured
• Enzyme Activation (drug effects)
• Hypertension (blood, metabolism, physiopathology)
• Leukocytes, Mononuclear (drug effects, enzymology, metabolism)
• Male
• Protein Kinase Inhibitors (pharmacology)
• Rats, Inbred SHR
• Rats, Sprague-Dawley
• rho-Associated Kinases (antagonists & inhibitors, metabolism)