AMPK activation is indispensible for the protective effects of caloric restriction in afterload-induced heart failure

Introduction: The postischemic myocardium is protected from cardiomyocyte loss, progressive heart failure and mitochondrial dysfunction by caloric restriction (CR). Recent data demonstrate that some CR effects are mediated by AMP-activated protein kinase (AMPK) activation by adipokines. Novel therapeutic options that mimic effects of CR, in addition to established heart failure therapy may improve myocardial function and outcome of heart surgery patients. Here, we investigated the effects of CR in an experimental model of afterload-induced cardiac dysfunction (aortic banding) on cardiac and mitochondrial function, apoptosis as well as adipokine-mediated activation of AMPK.

Methods: Male Wistar Rats (3 weeks) underwent ascending aortic banding/sham operation. After development of cardiac dysfunction (4 month) animals recieved standard chow or caloric restriction (–40%) for 12 weeks. Cardiac function was analyzed by echocardiography and tip catheter. Mitochondrial function (microrespirometry) adipokines and markers of apoptosis, cardiac load or metabolism were analyzed in tissue and blood samples (Western-Blot/qPCR/ELISA).

Results: Aortic banding results in severe cardiac dysfunction and reduced mitochondrial function. CR is sufficient to improve cardiac function (FS%, +7%, dp/dt +15%; BNP –50%) and reduce proapoptotic load (Bax –60%, Bcl-2 +50%). Changed adipokine patterns (Acrp30 +90%, RBP40 +70%) are associated with AMPK phosphorylation and stabilization of mitochondrial function. AMPK inhibition (Compound C 1mg/kg body weight i.p. via Alzet pumps) abolishes these protective effects.

Conclusion: AMPK activation is indispensable for the protective effects of CR afterload-induced cardiac dysfunction. Medical treatments that mimic these effects may be promising additive therapeutic strategies also in cardiac surgery patients.