PGC-1α regulates the mitochondrial antioxidant defense system in vascular endothelial cells

doi:10.1016/j.cardiores.2005.01.026

PGC-1α regulates the mitochondrial antioxidant defense system in vascular endothelial cells

^aCentro de Investigaciones Biológicas (Consejo Superior de Investigaciones Científicas), Ramiro de Maeztu, 9 28040, Madrid, Spain
^bCentro Nacional de Investigaciones Cardiovasculares (Instituto de Salud Carlos III), Ronda de Poniente, 5 Tres Cantos 28760, Madrid, Spain
^cInstituto “Reina Sofía de Investigaciones Nefrológicas”, Spain

*Corresponding authors. Centro Nacional de Investigaciones Cardiovasculares (Instituto de Salud Carlos III), Ronda de Poniente, 5 Tres Cantos 28760-Madrid, Spain. Tel.: +34 918061880x1140; fax: +34 918035258. Email address: mmonsalve{at}cnic.es

Received November 29, 2004.
Revision received January 17, 2005.
Accepted January 26, 2005.

Abstract

Objective: Mitochondrial production of oxidants contributes to a variety of pathological conditions including the vascular complications of diabetes, neurodegenerative diseases, and cellular senescence. We postulated that a transcriptional coactivator, peroxisome proliferator activated receptor-γ coactivator 1α (PGC-1α), a major regulator of oxidative metabolism and mitochondrial biogenesis, could be involved in the transcriptional regulation of the mitochondrial antioxidant defense system in vascular endothelial cells.

Methods and results: We show that PGC-1α is present in human, bovine, and mouse endothelial cells and positively modulates the expression of the mitochondrial detoxification system. Endothelial cells that overexpress PGC-1α show reduced accumulation of reactive oxygen species (ROS), increased mitochondrial membrane potential, and reduced apoptotic cell death both in basal and oxidative stress conditions. Downregulation of PGC-1α levels by siRNA reduces the expression of mitochondrial detoxification proteins.

Conclusions: These results unveil a novel regulatory pathway that links mitochondrial activity and mitochondrial oxidative stress protective systems. In addition, they suggest that PGC-1α could play a crucial protective role in vascular complications of diabetes, where the mitochondrial metabolism of glucose has been shown to result in oxidative stress and vascular endothelial cell dysfunction.

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