Abstract 19764: Role Of G-protein Coupled Receptor Kinase 2 In Cytokine-induced Cardiac Beta-adrenergic Receptor Desensitization
Cytokines cause left ventricular dysfunction and cardiomyopathy by altering cardiac mechanical function with their negative inotropic effects. A major factor contributing towards the negative inotropic effect is the pro-inflammatory cytokine-induced β-adrenergic receptor (βAR) desensitization. Although cytokine-induced βAR desensitization is well documented, little is known about mechanisms proximal to βAR. We hypothesize that cytokines contribute to cardiac dysfunction by regulating the βAR desensitization machinery. To determine the proximal mechanisms, transgenic mice with cardiac-specific overexpression of a pro-hypertrophic molecule, myotrophin (Myo-Tg) was used. The Myo-Tg mice are characterized by early initiation of cardiac hypertrophy that is associated with significant upregulation of inflammatory cytokines. Our studies show that progressive loss in the ability of βARs to activate cardiac adenylyl cyclase activity in Myo-Tg mice directly correlates to deteriorating cardiac function without changes in the plasma membrane βAR density. The progressive βAR desensitization observed in Myo-Tg mice is coupled with specific upregulation of G-protein coupled receptor kinase 2 (GRK2), PI3Kγ and GRK2-associated PI3K activity. Importantly, upregulation of GRK2 in Myo-Tg mice is not associated with changes in the circulating epinephrine/norepinephrine, but elevated levels of plasma inflammatory cytokines (TGFβ, TNFα, IL-6&IL-10). Treatment of cells with each of the cytokines independently shows that TNFα pre-treatment is sufficient to desensitize βARs. TNFα induced βAR desensitization is associated with specific upregulation of GRK2 leading to elevated βAR phosphorylation. In conclusion, our studies show that TNFα alone is sufficient and responsible for inducing βAR desensitization through upregulation of GRK2 suggesting the presence of a yet unidentified signaling cross-talk between TNFα and βAR desensitization machinery.
- © 2010 by American Heart Association, Inc.