Abstract 16000: Mitochondrial Regulation of Endothelial Function
Mitochondrial biogenesis as a contributing factor to health and disease has received increasing recognition. Impaired mitochondrial biogenesis and function is thought to contribute to the development of type 2 diabetes. We have previously linked PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1alpha)-induced mitochondrial biogenesis to endothelial cell stress adaptation in vivo. However, the role of PGC1α and PGC1α-induced mitochondrial biogenesis in endothelial dysfunction is not clear. To this end, we treated wild-type mice with angiotensin II and found downregulation of PGC1α and its target genes in the vasculature. To determine the implications of these findings, we generated transgenic mice with endothelium-specific PGC1α overexpression using the VE-cadherin promoter and showed that endothelial PGC1α protects mice from angiotensin II-induced hypertension. Because eNOS is important for endothelial homeostasis, we explored the role of eNOS and NO in the effects of PGC1α. We found that PGC1α overexpression by adenoviral-mediated gene transfer increased eNOS protein expression, eNOS phosphorylation, and NO release in cultured endothelial cells. Similar results were observed in endothelial cells isolated from endothelium-specific PGC1α transgenic mice. To causally address the link between eNOS and PGC1α, we crossed transgenic PGC1α mice with eNOS-/- mice to generate VECad-PGC1α/eNOS-/- mice. The increase in blood pressure in eNOS-/- mice was not attenuated by PGC-1α overexpression on the eNOS-/- background. Collectively, these data implicate downregulation of PGC-1α as a mechanism of endothelial dysfunction and highlight the role of the mitochondrion in controlling the endothelial response to environmental stress.
- © 2012 by American Heart Association, Inc.