Blood vessel formation is dependent on metabolic adaption in endothelial cells. Glucose and fatty acids are essential substrates for ATP and biomass production; however, the metabolism of other substrates remains poorly understood. Ketone bodies are important nutrients for cardiomyocytes during starvation or consumption of carbohydrate-restrictive diets. This raises the question whether cardiac endothelial cells would not only transport ketone bodies but also consume some of these to achieve their metabolic needs. Here, we report that cardiac endothelial cells are able to oxidize ketone bodies and that this enhances cell proliferation, migration, and vessel sprouting. Mechanistically, this requires succinyl-CoA:3-oxoacid-CoA transferase, a key enzyme of ketone body oxidation. Targeted metabolite profiling revealed that carbon from ketone bodies got incorporated into tricarboxylic acid cycle intermediates as well as other metabolites fueling biomass production. Elevation of ketone body levels by a high-fat, lowcarbohydrate ketogenic diet transiently increased endothelial cell proliferation in mouse hearts. Notably, in a mouse model of heart hypertrophy, ketogenic diet prevented blood vessel rarefication. This suggests a potential beneficial role of dietary intervention in heart diseases.
Sustained left ventricular hypertrophy (LVH) accelerates cardiac dysfunction and heart failure. Previous reports have suggested that activation of the peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent pathway is involved in development of cardiac hypertrophy. Thiazolidinediones (TZDs) such as pioglitazone activate PPARgamma and are clinically used as antidiabetics. Given inconsistent reports regarding effects of TZDs on LVH, we examined in the present study the influence of pioglitazone on LVH in a rat model of aortic banding. Aortic banding was induced in rats by clipping the ascending aorta. Animals received pioglitazone (3 mg/kg/day) or placebo. Echocardiographic, hemodynamic, histological, and biochemical measurements were performed after 2 and 4 weeks. Pressure gradient was comparable between pioglitazone- and placebo-treated animals after 2 and 4 weeks. Left ventricular function was not different between the groups. In sham as well as in banded animals, LV/body weight ratio was increased in pioglitazone- as compared to placebo-treated animals after 2 and 4 weeks. Furthermore, an increase in myocyte size and atrial natriuretic factor was observed in pioglitazone- compared to placebo-treated animals 4 weeks after aortic banding as well. The results of this study demonstrate that activation of PPARgamma via pioglitazone does not protect the myocardium from pressure overload-induced LVH in a rat model of aortic banding. The findings rather indicate a pro-hypertrophic effect of pioglitazone treatment after aortic banding.
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