Copyright © 2005, European Society of Cardiology
PGC-1
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
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-
coactivator 1
(PGC-1), 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-1 is present in human, bovine, and mouse endothelial cells and positively modulates the expression of the mitochondrial detoxification system. Endothelial cells that overexpress PGC-1 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-1 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-1 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.
KEYWORDS PGC-1; Endothelium; Oxidative stress; Mitochondria; Glucose
Time for primary review 28 days
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