| First Author | Vasudevan NT | Year | 2013 |
| Journal | Circulation | Volume | 128 |
| Issue | 4 | Pages | 377-87 |
| PubMed ID | 23785004 | Mgi Jnum | J:218735 |
| Mgi Id | MGI:5618245 | Doi | 10.1161/CIRCULATIONAHA.113.003183 |
| Citation | Vasudevan NT, et al. (2013) Gbetagamma-independent recruitment of G-protein coupled receptor kinase 2 drives tumor necrosis factor alpha-induced cardiac beta-adrenergic receptor dysfunction. Circulation 128(4):377-87 |
| abstractText | BACKGROUND: Proinflammatory cytokine tumor necrosis factor-alpha (TNFalpha) induces beta-adrenergic receptor (betaAR) desensitization, but mechanisms proximal to the receptor in contributing to cardiac dysfunction are not known. METHODS AND RESULTS: Two different proinflammatory transgenic mouse models with cardiac overexpression of myotrophin (a prohypertrophic molecule) or TNFalpha showed that TNFalpha alone is sufficient to mediate betaAR desensitization as measured by cardiac adenylyl cyclase activity. M-mode echocardiography in these mouse models showed cardiac dysfunction paralleling betaAR desensitization independent of sympathetic overdrive. TNFalpha-mediated betaAR desensitization that precedes cardiac dysfunction is associated with selective upregulation of G-protein coupled receptor kinase 2 (GRK2) in both mouse models. In vitro studies in beta2AR-overexpressing human embryonic kidney 293 cells showed significant betaAR desensitization, GRK2 upregulation, and recruitment to the betaAR complex following TNFalpha. Interestingly, inhibition of phosphoinositide 3-kinase abolished GRK2-mediated betaAR phosphorylation and GRK2 recruitment on TNFalpha. Furthermore, TNFalpha-mediated betaAR phosphorylation was not blocked with betaAR antagonist propranolol. Additionally, TNFalpha administration in transgenic mice with cardiac overexpression of Gbetagamma-sequestering peptide betaARK-ct could not prevent betaAR desensitization or cardiac dysfunction showing that GRK2 recruitment to the betaAR is Gbetagamma independent. Small interfering RNA knockdown of GRK2 resulted in the loss of TNFalpha-mediated betaAR phosphorylation. Consistently, cardiomyocytes from mice with cardiac-specific GRK2 ablation normalized the TNFalpha-mediated loss in contractility, showing that TNFalpha-induced betaAR desensitization is GRK2 dependent. CONCLUSIONS: TNFalpha-induced betaAR desensitization is mediated by GRK2 and is independent of Gbetagamma, uncovering a hitherto unknown cross-talk between TNFalpha and betaAR function, providing the underpinnings of inflammation-mediated cardiac dysfunction. |
