Left Ventricular Function in Heart Failure Can Be Improved by AMPK-Activation via Acrp30 Signaling

Objectives: Direct myocardial effects of adipokines may be important for improvement of myocardial dysfunction. Caloric restriction has been shown to extend lifespan and to improve function in lipotoxic cardiomyopathy via AMPK-dependent mechanisms. Here we investigated effects on left ventricular function by caloric restriction and importance of upstream and downstream signaling of AMPK activation for functional and mitochondrial recovery of the dysfunctional heart.

Methods: We ligated the left coronary artery or performed sham operation in young rats. After development of cardiac dysfunction (4 weeks) animals were matched in groups (echocardiography, LV function) and fed a control diet or caloric restriction (CR, -40% calories, 3 months) with or without AMPK inhibition. a2 or a1 AMPK knockout mice underwent the same procedures. H9C2 cardiomyocytes with stable a2 or a1 AMPK knockdown were utilized to analyze adiponectin-mediated signaling. Cardiac function, mitochondrial (mito) function and mito biogenesis were analyzed in tissue lysates and cardiomyocytes.

Results: Cardiac dysfunction leads to significant decrease in cardiac and mitochondrial function and increases apoptotic cell death. Short-term CR improves LV function and increases mitochondrial function and biogenesis, which is associated with chronic AMPK activation (a2>a1 isoform). Apoptotic activation is reduced. Inhibition of AMPK activation (compound C) prevents cardiac and mito functional recovery. a2 but not a1 AMPK knockout mice were unable to benefit from CR. AMPK is activated by Acrp30 via adiponectin receptor 1 and T-cadherin via LKB-1- and CaMKKβ1-dependent mechanisms. Activation of AMPK is indispensable for reduction of apoptosis, improved cell viability, anti-oxidant defense and preserved mitochondrial function and biogenesis in cardiomyocytes. Knockout of individual AMPK isoforms was partly compensated by upregulation of the respective other AMPK isoform.

Conclusion: The dysfunctional myocardium can be protected from progressive cardiomyocyte loss, progressive heart failure and mitochondrial dysfunction by (a2) AMPK activation. Selective therapeutic targeting might be useful for preventing or treating ischemia, obesity, senescence or cardioplegia-associated loss of cardiac and mitochondrial function.

No conflict of interest has been declared by the author(s).