Shear stress-induced Ang II AT1 receptor activation: G-protein dependent and independent mechanisms

Author(s)

Barauna, Valerio G. ^[1] ; Magalhaes, Flavio C. ^[2] ; Campos, Luciene C. G. ^[1] ; Reis, Rosana I. ^[3] ; Kunapuli, Satya P. ^[4] ; Costa-Neto, Claudio M. ^[3] ; Miyakawa, Ayumi A. ^[1] ; Krieger, Jose E. ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Med, Lab Genet & Mol Cardiol, Heart Inst InCor, BR-05403000 Sao Paulo - Brazil

^[2] Fed Univ Jequitinhonha & Mucuri Valleys, Dept Phys Educ, Multicentr Program Postgrad Physiol Sci, BR-39100000 Diamantina - Brazil

^[3] Fac Med Ribeirao Preto, Dept Biochem & Immunol, BR-14049900 Ribeirao Preto - Brazil

^[4] Temple Univ, Dept Physiol & Pharmacol, Sch Med, Philadelphia, PA 19122 - USA

• Document type: Journal article
• Source: Biochemical and Biophysical Research Communications; v. 434, n. 3, p. 647-652, MAY 10 2013.
• Web of Science Citations: 21

Abstract

Mechanotransduction enables cells to sense and respond to stimuli, such as strain, pressure and shear stress (SS), critical for maintenance of cardiovascular homeostasis or pathological states. The angiotensin II type 1 receptor (AT1R) was the first G protein-coupled receptor described to display stretch-induced activation in cardiomyocytes independent of its ligand Ang II. Here, we assessed whether SS (15 dynes/cm(2), 10 min), an important mechanical force present in the cardiovascular system, activates AT1R independent of its ligand. SS induced extracellular signal-regulated kinase (ERIC) activation, used as a surrogate of AT1R activation, in Chinese hamster ovary cells expressing the AT1R (CHO + AT1) but not in wild type cells (CHO). AT1R dependent SS-induced ERIC activation involves Ca2+ inflow and activation of G alpha q since Ca2+ chelator EGTA or G alpha q-specific inhibitor YM-254890 decreased SS-induced ERK activation. On the other hand, the activation of JAK-2 and Src, two intracellular signaling molecules independent of G protein activation, were not differently modulated in the presence of AT1R. Also, ERIC activation by SS was observed in CHO cells expressing the mutated AT1R DRY/AAY, which has impaired ability to activate G alpha q dependent intracellular signaling. Altogether we provided,evidence that SS activates AT1R in the absence of its ligand by both a G protein-dependent and -independent pathways. The biological relevance of these observations deserves to be further investigated since the novel mechanisms described extend the knowledge of the activation of GPCRs independent of its traditional ligand. (C) 2013 Elsevier Inc. All rights reserved. (AU)

• FAPESP's process: 01/00009-0 - An integrated approach for the dissection of primary hypertension: molecular and functional characterization of the cardiovascular system
• Grantee: Eduardo Moacyr Krieger
• Support Opportunities: Research Projects - Thematic Grants