Abstract 3607: Adiponectin-deficiency Contributes to Exacerbated Cardiac Dysfunction Following Chronic Pressure Overload Through Disruption of AMPK-dependent Angiogenesis
Background: Accumulating evidence indicates that adiponectin protects against pathological cardiac remodeling by directly acting on the myocardium. However, the underlying molecular mechanism of cardioprotection by adiponectin has not been fully elucidated. Because disruption of angiogenesis during heart growth leads to contractile dysfunction and heart failure, we hypothesized that impaired angiogenic response contributes to exacerbated cardiac remodeling in response to pressure overload under conditions of adiponectin-deficiency.
Methods: Adiponectin-knockout (APN-KO) and wild-type (WT) mice were subjected to pressure overload caused by transverse aortic constriction (TAC). Cardiac function and structure were assessed by echocardiography and Masson’s trichrome staining. Myocardial capillary density was evaluated by staining with anti-CD31 antibody. Angiogenesis-related molecules were assessed by Western blot analysis.
Results: APN-KO mice showed exacerbated cardiac hypertrophy, pulmonary congestion, left ventricular (LV) interstitial fibrosis and LV systolic dysfunction compared with WT mice at 3 weeks after TAC surgery. At 2 weeks after TAC, capillary density in the myocardium was significantly reduced in APN-KO mice, which was accompanied by decreased expression of hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF), and attenuated phosphorylation of AMPK. Inhibition of AMPK by compound C resulted in increased LV systolic dysfunction and reduced myocardial capillary density in WT mice after TAC surgery, which was associated with reduced expression HIF-1 and VEGF. Of note, the adverse effects of AMPK inhibition on cardiac function and angiogenic response following TAC were diminished in APN-KO mice relative to WT mice.
Conclusions: These results indicate that adiponectin deficiency can accelerate the transition from cardiac hypertrophy to heart failure during pressure overload through disruption of angiogenesis involving AMPK signaling.