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PGC-1alpha is a key regulator of glucose-induced proliferation and migration in vascular smooth muscle cells.

ABSTRACT: 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.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.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.

SUBMITTER: Zhu L

PROVIDER: S-EPMC2615131 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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PGC-1alpha is a key regulator of glucose-induced proliferation and migration in vascular smooth muscle cells.

Zhu Lingyun L 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

PloS one 20090114 1

<h4>Background</h4>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 ...[more]

PMID: 19142226

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Project description:Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in the pentose phosphate pathway and a major source of nicotinamide adenine dinucleotide phosphate reduced (NADPH), which regulates numerous enzymatic (including glutathione reductase and NADPH oxidase that, respectively, generates reduced glutathione and reactive oxygen species) reactions involved in various cellular actions, yet its physiological function is seldom investigated. We, however, recently showed that inhibiting G6PD causes precontracted coronary artery (CA) to relax in an endothelium-derived relaxing factor- and second messenger-independent manner. Here we assessed the role of G6PD in regulating CA contractility. Treating bovine CAs for 20 min with potassium chloride (KCl; 30 mM), amphotericin B (50 μM), or U46619 (100 nM) significantly (p < 0.05) increased both G6PD activity and glucose flux through the pentose phosphate pathway. The effect was Ca(2+) independent, and there was a corresponding increase in protein kinase C (PKC) activity. Activation of G6PD by KCl was blocked by the PKCδ inhibitor rottlerin (10 μM) or by knocking down PKCδ expression using siRNA. Phorbol 12, 13-dibutyrate (10 μM), a PKC activator, significantly increased G6PD phosphorylation and activity, whereas single (S210A, T266A) and double (S210A/T266A) mutations at sites flanking the G6PD active site significantly inhibited phosphorylation, shifted the isoelectric point, and reduced enzyme activity. Knocking down G6PD decreased NADPH and reactive oxygen species generation, and reduced KCl-evoked increases in [Ca(2+)](i) and myosin light chain phosphorylation, thereby reducing CA contractility. Similarly, aortas from G6PD-deficient mice developed less KCl/phorbol 12, 13-dibutyrate-evoked force than those from their wild-type littermates. Conversely, overexpression of G6PD augmented KCl-evoked increases in [Ca(2+)](i), thereby augmenting CA contraction. Our findings demonstrate that G6PD activity and NADPH is increased in activated CA in a PKCδ-dependent manner and that G6PD modulates Ca(2+) entry and CA contractions evoked by membrane depolarization.

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PGC-1alpha is a key regulator of glucose-induced proliferation and migration in vascular smooth muscle cells.

Publications

PGC-1alpha is a key regulator of glucose-induced proliferation and migration in vascular smooth muscle cells.

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