PGC-1alpha is a key regulator of glucose-induced proliferation and migration in vascular smooth muscle cells.
BACKGROUND
Atherosclerosis is a complex pathological condition caused by a number of mechanisms including the accelerated proliferation of vascular smooth muscle cells (VSMCs). Diabetes is likely to be an important risk factor for atherosclerosis, as hyperglycemia induces vascular smooth muscle cell (VSMC) proliferation and migration and may thus contribute to the formation of atherosclerotic lesions. This study was performed to investigate whether PGC-1alpha, a PPARgamma coactivator and metabolic master regulator, plays a role in regulating VSMC proliferation and migration induced by high glucose.


RESULTS
PGC-1alpha mRNA levels are decreased in blood vessel media of STZ-treated diabetic rats. In cultured rat VSMCs, high glucose dose-dependently inhibits PGC-1alpha mRNA expression. Overexpression of PGC-1alpha either by infection with adenovirus, or by stimulation with palmitic acid, significantly reduces high glucose-induced VSMC proliferation and migration. In contrast, suppression of PGC-1alpha by siRNA mimics the effects of glucose on VSMCs. Finally, mechanistic studies suggest that PGC-1alpha-mediated inhibition of VSMC proliferation and migration is regulated through preventing ERK1/2 phosphorylation.


CONCLUSIONS
These results indicate that PGC-1alpha is a key regulator of high glucose-induced proliferation and migration in VSMCs, and suggest that elevation of PGC-1alpha in VSMC could be a useful strategy in preventing the development of diabetic atherosclerosis.
Zhu
Lingyun
L
Jiangsu Diabetes Center, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, People's Republic of China.
Sun
Guoxun
G
Zhang
Hongjie
H
Zhang
Yan
Y
Chen
Xi
X
Jiang
Xiaohong
X
Jiang
Xueyuan
X
Krauss
Stefan
S
Zhang
Junfeng
J
Xiang
Yang
Y
Zhang
Chen-Yu
CY
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications; D005786:Gene Expression Regulation / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D051381:Rats; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D048052:Mitogen-Activated Protein Kinase 3; D005947:Glucose