Cardiac myocyte β3-adrenergic receptors prevent myocardial fibrosis by modulating oxidant stress-dependent paracrine signaling. (6th July 2017)

• Record Type: Journal Article
• Authors: Hermida, Nerea; Michel, Lauriane; Esfahani, Hrag; Dubois-Deruy, Emilie; Hammond, Joanna; Bouzin, Caroline; Markl, Andreas; Colin, Henri; Steenbergen, Anne Van; De Meester, Christophe; Beauloye, Christophe; Horman, Sandrine; Yin, Xiaoke; Mayr, Manuel; Balligand, Jean-Luc
• Is Part Of: European heart journal. Volume 39:Number 10(2018)
• Page Start: 888
• Page End: 898
• Publication Date: 2017-07-06
• Subjects: Myocardial remodeling -- Fibrosis -- Catecholamines -- Beta3 adrenergic receptor -- Nitric oxide -- Oxidant stress; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehx366
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Aims: Human and mouse cardiac beta3-adrenergic receptors (beta3AR) exert antipathetic effects to those of beta1-2AR stimulation. We examined their role in modulating myocardial remodelling, particularly fibrosis in response to haemodynamic stress. Methods and results: Mice with cardiac myocyte-specific expression of beta3AR ( ADRB3 -tg) or tamoxifen-inducible homozygous deletion (c- Adrb3 -ko, with loxP-targeted Adrb3 ) were submitted to transaortic constriction. A superfusion assay was used for proteomic analysis of paracrine mediators between beta3AR-expressing cardiac myocytes and cardiac fibroblasts cultured separately. We show that cardiac beta3AR attenuate myocardial fibrosis in response to haemodynamic stress. Interstitial fibrosis and collagen content were reduced in ADRB3 -tg, but augmented in c- Adrb3 -ko. ADRB3 and collagen ( COL1A1 ) expression were also inversely related in ventricular biopsies of patients with valve disease. Incubation of cardiac fibroblasts with media conditioned by hypertrophic myocytes induced fibroblast proliferation, myo-differentiation, and collagen production. These effects were abrogated upon ADRB3 expression in myocytes. Comparative shotgun proteomic analysis of the myocyte secretomes revealed a number of factors differentially regulated by beta3AR, among which connective tissue growth factor [CTGF (CCN2)] was prominently reduced. CTGF was similarly reduced in stressed hearts from ADRB3 -tg, but increased in hearts from c- Adrb3 -ko mice. CTGF expression was mediated by reactive oxygen species production which was reduced by ADRB3 expression in vitro and in vivo . This antioxidant and anti-fibrotic effect involved beta3AR coupling to the neuronal isoform of nitric oxide synthase (nNOS) in cardiac myocytes, as both were abrogated upon nNOS inhibition or Nos1 homozygous deletion. Conclusion: Cardiac beta3AR protect from fibrosis in response to haemodynamic stress by modulating nitric oxide and oxidant stress-dependent paracrine signaling to fibroblasts. Specific agonism at beta3AR may offer a new therapeutic modality to prevent cardiac fibrosis.