RhoA/Rho-cinase signaling pathway in the vascular smooth muscle from mice with angiotensin II-induced hypertension: interaction with reactive oxygen species, interleukin-6 (IL-6) and JAK/STAT activation

• Grant number: 06/01773-0
• Support Opportunities: Scholarships abroad - New Frontiers
• Effective date (Start): September 01, 2006
• Effective date (End): August 31, 2007
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Rita de Cassia Aleixo Tostes Passaglia
• Grantee: Rita de Cassia Aleixo Tostes Passaglia
• Host Investigator: R. Clinton Webb
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Research place: Georgia Regents University, United States

Abstract

RhoA/Rho-cinase signaling pathway in the vascular smooth muscle from mice with angiotensin II-induced hypertension: interaction with reactive oxygen species, interleukin-6 (IL-6) and JAK/STAT activation. The mechanisms responsible for elevated vascular resistance and increased vascular reactivity in hypertension are complex. Considerable attention has focused on the possibility that the increase in peripheral resistance is caused by an alteration in vascular smooth muscle that makes it more sensitive to normal stimuli. Recent experimental observations (1-3) suggest that this increased sensitivity reflects, at least in part, an abnormal regulation of myosin light chain (MLC) phosphorylation by RhoA/Rho-kinase (calcium sensitization). In this signal transduction system, Rho-kinase, after activation by RhoA, phosphorylates MLC phosphatase (also known as, myosin phosphatase) to inhibit its activity. This results in the maintenance of phosphorylated MLC, thus promoting the binding of actin and myosin for force generation. This research proposal will extend our understanding of the RhoA/Rho-kinase signaling system in vascular smooth muscle from hypertensive mice. The research will be guided by the working hypothesis that augmented vascular reactivity in angiotensin II-induced hypertension occurs by a two-step mechanism to increase the functional activity of the RhoA/Rho-kinase system: 1) during the early phase of blood pressure elevation, angiotensin II stimulates superoxide production leading to transactivation of the epidermal growth factor receptor (EGFR) and subsequent stimulation of RhoA/Rho-kinase to cause vasoconstriction; and 2) during the established phase of blood pressure elevation, angiotensin II increases interleukin-6 (IL-6) in plasma and tissue leading to activation of janus kinases (JAK) and signal transducers and activators of transcription factors (STAT) and increased expression of components of the RhoA/Rho-kinase cascade and maintained vasoconstriction. This working hypothesis will be tested by three specific aims: #1: To test the hypothesis that during the early phase of blood pressure elevation in angiotensin II-induced hypertension, the octapeptide stimulates RhoA/Rho-kinase signaling via superoxide activation of the EGFR. Components of the proposed cascade will be measured in blood vessels from hypertensive and normotensive mice. A pharmacological analysis of RhoA/Rho-kinase signaling (contractile responses, calcium sensitization) with respect to angiotensin II-induced superoxide generation to stimulate the EGFR will be performed. #2: To test the hypothesis that during the maintained phase of angiotensin II-induced hypertension, the octapeptide and IL-6 increase expression of components of the RhoA/Rho-kinase signaling pathway via activation of JAK/STAT. Components of the RhoA/Rho-kinase and JAK/STAT signaling pathway will be measured in wild-type and IL-6 knock out mice during the maintained phase of angiotensin II-induced hypertension. A pharmacological analysis of RhoA/Rho-kinase signaling (contractile responses, calcium sensitization) with respect to angiotensin II-induced JAK/STAT signaling will be performed. #3: To test the hypothesis that augmented RhoA/Rho-kinase signaling is not related to blood pressure per se in angiotensin II-induce hypertension. The influence of blood pressure per se in angiotensin II-induced hypertension will be analyzed by pharmacologically lowering blood pressure and by protecting a vascular bed from the hemodynamic load. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GIACHINI, F. R. C.; CARNEIRO, F. S.; LIMA, V. V.; CARNEIRO, Z. N.; BRANDS, M. W.; WEBB, R. C.; TOSTES, R. C.. A key role for Na+/K+-ATPase in the endothelium-dependent oscillatory activity of mouse small mesenteric arteries. Brazilian Journal of Medical and Biological Research, v. 42, n. 11, p. 1058-1067, NOV 2009. (06/01773-0)

GIACHINI, FERNANDA R. C.; ZEMSE, SAIPRASAD M.; CARNEIRO, FERNANDO S.; LIMA, VICTOR V.; CARNEIRO, ZIDONIA N.; CALLERA, GLAUCIA E.; ERGUL, ADVIYE; WEBB, R. CLINTON; TOSTES, RITA C.. Interleukin-10 attenuates vascular responses to endothelin-1 via effects on ERK1/2-dependent pathway. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, v. 296, n. 2, p. H489-H496, FEB 2009. (06/01773-0)