Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha overexpression prevents endothelial apoptosis by increasing ATP/ADP translocase activity.
OBJECTIVE
Fatty acids increase reactive oxygen species generation and cell apoptosis in endothelial cells. The peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1alpha) is a transcriptional coactivator that increases mitochondrial biogenesis and fatty acid oxidation in various cells. This study was undertaken to investigate the possible preventive effect of PGC-1alpha on endothelial apoptosis and its molecular mechanism.


RESULTS
Treatment with linoleic acid in cultured human aortic endothelial cells increased reactive oxygen species generation and cell apoptosis. These effects appeared to be mediated by increases in cytosolic fat metabolites, ie, fatty acyl CoA, diacylglycerol, and ceramide, and consequent decreases in ATP/ADP translocase activity of adenine nucleotide translocator. Adenoviral overexpression of PGC-1alpha prevented linoleic acid-induced increases in reactive oxygen species generation and cell apoptosis in human aortic endothelial cells by increasing fatty acid oxidation, decreasing diacylglycerol and ceramide, and increasing ATP/ADP translocase activity. In isolated aorta, PGC-1alpha overexpression prevented linoleic acid-induced decrease in endothelium-dependent vasorelaxation, and this effect was abolished by adenine nucleotide translocator1 shRNA.


CONCLUSIONS
PGC-1alpha regulates reactive oxygen species generation and apoptosis in endothelial cells by increasing fatty acid oxidation and enhancing ATP/ADP translocase activity. Measures to increase PGC-1alpha expression or ATP/ADP translocase activity in vascular cells may aid in the prevention or treatment of atherosclerosis.
Won
Jong Chul
JC
Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea.
Park
Joong-Yeol
JY
Kim
Yun Mi
YM
Koh
Eun Hee
EH
Seol
Somi
S
Jeon
Byeong Hwan
BH
Han
Jin
J
Kim
Jung Ran
JR
Park
Tae-Sik
TS
Choi
Cheol Soo
CS
Lee
Woo Je
WJ
Kim
Min-Seon
MS
Lee
In-Kyu
IK
Youn
Jang Hyun
JH
Lee
Ki-Up
KU
D000214:Acyl Coenzyme A / Q000378:metabolism; D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D005227:Fatty Acids / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019787:Linoleic Acid / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation; D014664:Vasodilation
D000214:Acyl Coenzyme A; D033741:Adenine Nucleotide Translocator 1; D002518:Ceramides; D004075:Diglycerides; D005227:Fatty Acids; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D019787:Linoleic Acid