Abstract 17953: G&rtf-inf-start;Beta Gamma&rtf-inf-end; Independent Recruitment Of G-protein Coupled Receptor Kinase 2 Drives TNF Alpha-induced Cardiac Beta-adrenergic Receptor Dysfunction
Inflammatory cytokine tumor necrosis factor α (TNFα) induces β-adrenergic receptor (βAR) desensitization, but mechanisms proximal to the receptor in contributing to cardiac dysfunction are unknown. We hypothesize that TNFα contribute to cardiac dysfunction by regulating βAR desensitization. Two pro-inflammatory transgenic (Tg) mouse models with cardiac overexpression of Myotrophin or TNFα showed that TNFα alone is sufficient to mediate βAR desensitization as shown by cardiac adenylyl cyclase activity (38% reduction in Myo-Tg; 30% reduction in TNF-Tg). M-mode echocardiography showed significant cardiac dysfunction (% FS: Control: 57.6, Myo-Tg: 46.3, EF: Control: 72%, TNFα-Tg: 50%) paralleling βAR desensitization independent of sympathetic overdrive. TNFα-mediated βAR desensitization is associated with selective upregulation of G-protein coupled receptor kinase 2 (GRK2) (2.5 fold in Myo-Tg, 1.7 fold in TNF-Tg). In vitro studies showed significant βAR desensitization (confocal figure), GRK2 upregulation and recruitment to the βAR complex upon TNFα. Inhibition of PI3K abolished GRK2 recruitment and βAR phosphorylation upon TNFα. TNFα-mediated βAR phosphorylation was not blocked with βAR antagonist propranolol. TNFα administration in transgenic mice with cardiac overexpression of βARKct (GRK2ct) could not prevent βAR desensitization (∼ 30% reduction in βARK-ct Tg) or cardiac dysfunction (% FS: control, 58%, βARK-ct Tg, 38%) showing that GRK2 recruitment to the βAR is Gβγ independent. siRNA knock down of GRK2 resulted in loss of TNFα-mediated βAR phosphorylation. Cardiomyocytes from cardiac-specific GRK2 knock out mice normalized the TNFα-mediated loss in contractility showing that TNFα-induced βAR desensitization is GRK2 dependent (see figure). In conclusion, TNFα-induced βAR desensitization is mediated by GRK2, independent of Gβγ, unraveling a novel cross-talk between TNFα and βARs during inflammation-mediated cardiac dysfunction.
- Cardiac hypertrophy
- Signal transduction
- Beta-adrenergic receptor agonists
- Receptor-mediated signaling
- © 2012 by American Heart Association, Inc.