title: Gq-coupled receptor agonists mediate cardiac hypertrophy via the vasculature.
abstract: The Gq-coupled receptor-signaling pathway has been implicated in the cardiac hypertrophic response to stress, but little is actually known about the contributions of Gq signaling in either the heart or the vasculature. Therefore, we developed a line of transgenic mice that express a peptide inhibitor of Gq (GqI) in vascular smooth muscle to determine if vascular Gq signaling was important in the cardiac hypertrophic response. After chronic administration of the Gq agonists phenylephrine, serotonin, and angiotensin II, we observed an attenuation of mean arterial blood pressure and an inhibition of cardiac hypertrophy in the transgenic mice with vascular-specific GqI expression. In contrast, cardiac GqI peptide expression did not attenuate the hypertension or the cardiac hypertrophy. Importantly, all mice were capable of cardiac hypertrophy, because direct beta-adrenergic receptor stimulation induced a similar level of hypertrophy in both lines of transgenic mice. This clearly suggests that after chronic Gq-coupled receptor agonist administration, it is the hypertensive state induced by vascular Gq activation that mediates remodeling of the heart, rather than direct stimulation of cardiac Gq-coupled receptors. Thus, the contribution of vascular Gq-coupled signaling to the development of cardiac hypertrophy is significant and suggests that expression of the GqI peptide is a novel therapeutic strategy to lower Gq-mediated hypertension and cardiac hypertrophy.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Janelle R
authors.initials: JR
authors.lastname: Keys
authors.forename: Emily A
authors.initials: EA
authors.lastname: Greene
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Eckhart
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000503:physiopathology*; D002395:Catecholamines / Q000097:blood; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D020962:Heterotrimeric GTP-Binding Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015918:Infusion Pumps, Implantable; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013995:Time; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D002395:Catecholamines; D008840:Microfilament Proteins; D009124:Muscle Proteins; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C058992:Tagln protein, mouse; D014662:Vasoconstrictor Agents; C051615:transgelin; D000804:Angiotensin II; D010656:Phenylephrine; D012701:Serotonin; D020928:Mitogen-Activated Protein Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins