Role of PGC-1α in Vascular Regulation: Implications for Atherosclerosis.
Mitochondrial dysfunction results in high levels of oxidative stress and mitochondrial damage, leading to disruption of endothelial homeostasis. Recent discoveries have clarified several pathways, whereby mitochondrial dysregulation contributes to endothelial dysfunction and vascular disease burden. One such pathway centers around peroxisome proliferator receptor-γ coactivator 1α (PGC-1α), a transcriptional coactivator linked to mitochondrial biogenesis and antioxidant defense, among other functions. Although primarily investigated for its therapeutic potential in obesity and skeletal muscle differentiation, the ability of PGC-1α to alter a multitude of cellular functions has sparked interest in its role in the vasculature. Within this context, recent studies demonstrate that PGC-1α plays a key role in endothelial cell and smooth muscle cell regulation through effects on oxidative stress, apoptosis, inflammation, and cell proliferation. The ability of PGC-1α to affect these parameters is relevant to vascular disease progression, particularly in relation to atherosclerosis. Upregulation of PGC-1α can prevent the development of, and even encourage regression of, atherosclerotic lesions. Therefore, PGC-1α is poised to serve as a promising target in vascular disease. This review details recent findings related to PGC-1α in vascular regulation, regulation of PGC-1α itself, the role of PGC-1α in atherosclerosis, and therapies that target this key protein.
From the Department of Physiology (A.O.K., D.D.G.), Division of Cardiology, Department of Medicine (D.S.C., K.A.-A., D.D.G.), and Cardiovascular Center (A.O.K., D.S.C., K.A.-A., D.D.G.), Medical College of Wisconsin, Milwaukee; and Department of Veterans Administration Medical Center, Milwaukee, WI (D.D.G.).
Andrew O
AO
Kadlec
From the Department of Physiology (A.O.K., D.D.G.), Division of Cardiology, Department of Medicine (D.S.C., K.A.-A., D.D.G.), and Cardiovascular Center (A.O.K., D.S.C., K.A.-A., D.D.G.), Medical College of Wisconsin, Milwaukee; and Department of Veterans Administration Medical Center, Milwaukee, WI (D.D.G.).
Dawid S
DS
Chabowski
From the Department of Physiology (A.O.K., D.D.G.), Division of Cardiology, Department of Medicine (D.S.C., K.A.-A., D.D.G.), and Cardiovascular Center (A.O.K., D.S.C., K.A.-A., D.D.G.), Medical College of Wisconsin, Milwaukee; and Department of Veterans Administration Medical Center, Milwaukee, WI (D.D.G.).
Karima
K
Ait-Aissa
From the Department of Physiology (A.O.K., D.D.G.), Division of Cardiology, Department of Medicine (D.S.C., K.A.-A., D.D.G.), and Cardiovascular Center (A.O.K., D.S.C., K.A.-A., D.D.G.), Medical College of Wisconsin, Milwaukee; and Department of Veterans Administration Medical Center, Milwaukee, WI (D.D.G.). dgutt@mcw.edu.
David D
DD
Gutterman
D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism*; D058226:Plaque, Atherosclerotic; D015398:Signal Transduction
C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
apoptosis; atherosclerosis; cardiovascular disease; endothelium; oxidative stress