title: Regulator of G protein signaling 2 is a functionally important negative regulator of angiotensin II-induced cardiac fibroblast responses.
abstract: Cardiac fibroblasts play a key role in fibrosis development in response to stress and injury. Angiotensin II (ANG II) is a major profibrotic activator whose downstream effects (such as phospholipase Cβ activation, cell proliferation, and extracellular matrix secretion) are mainly mediated via G(q)-coupled AT(1) receptors. Regulators of G protein signaling (RGS), which accelerate termination of G protein signaling, are expressed in the myocardium. Among them, RGS2 has emerged as an important player in modulating G(q)-mediated hypertrophic remodeling in cardiac myocytes. To date, no information is available on RGS in cardiac fibroblasts. We tested the hypothesis that RGS2 is an important regulator of ANG II-induced signaling and function in ventricular fibroblasts. Using an in vitro model of fibroblast activation, we have demonstrated expression of several RGS isoforms, among which only RGS2 was transiently upregulated after short-term ANG II stimulation. Similar results were obtained in fibroblasts isolated from rat hearts after in vivo ANG II infusion via minipumps for 1 day. In contrast, prolonged ANG II stimulation (3-14 days) markedly downregulated RGS2 in vivo. To delineate the functional effects of RGS expression changes, we used gain- and loss-of-function approaches. Adenovirally infected RGS2 had a negative regulatory effect on ANG II-induced phospholipase Cβ activity, cell proliferation, and total collagen production, whereas RNA interference of endogenous RGS2 had opposite effects, despite the presence of several other RGS. Together, these data suggest that RGS2 is a functionally important negative regulator of ANG II-induced cardiac fibroblast responses that may play a role in ANG II-induced fibrosis development.
authors.affiliation: Cardiovascular Research Center, Rhode Island Hospital and Alpert Medical School of Brown Univ., 1 Hoppin St., Providence, RI 02903, USA. peng_zhang@brown.edu
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Jialin
authors.initials: J
authors.lastname: Su
authors.forename: Michelle E
authors.initials: ME
authors.lastname: King
authors.forename: Angel E
authors.initials: AE
authors.lastname: Maldonado
authors.forename: Cindy
authors.initials: C
authors.lastname: Park
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mende
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000166:cytology; D058628:Myofibroblasts / Q000187:drug effects; D054799:Phospholipase C beta / Q000378:metabolism; D020710:RGS Proteins / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000502:physiology
chemical_list: D020710:RGS Proteins; C514563:RGS2 protein, rat; D000804:Angiotensin II; D003094:Collagen; D054799:Phospholipase C beta