A novel role of endothelial autophagy as a regulator of myocardial fatty acid oxidation.

Abstract

We sought to determine if endothelial autophagy affects myocardial energy metabolism. We used isolated working mouse hearts to compare cardiac function, energy metabolism, and ischemic response of hearts from endothelial cell-specific ATG7 knockout (EC-ATG7^-/-) mice to hearts from their wild-type littermates. We also conducted gene analyses on human umbilical vein endothelial cells incubated with scrambled small interfering RNA or small interfering ATG7. In the presence of insulin, working hearts from EC-ATG7^-/- mice, relative to those from wild-type littermates, exhibited greater reductions in insulin-associated palmitate oxidation indicating a diminished reliance on fatty acids as a fuel source. Likewise, palmitate oxidation was markedly lower in the hearts of EC-ATG7^-/- mice versus wild-type mice during reperfusion of ischemic hearts. Although hearts from EC-ATG7^-/- mice revealed significantly lower triacylglycerol content compared with those from wild-type mice, ATG7-silenced human umbilical vein endothelial cells demonstrated appreciably lower fatty acid binding protein 4 and 5 expression relative to those treated with scrambled small interfering RNA. Disruption of endothelial autophagy reduces cardiac fatty acid storage and dampens reliance on fatty acid oxidation as a cardiac fuel source. The autophagy network represents a novel target for designing new strategies aimed at resetting perturbed myocardial bioenergetics.