PGC-1α Inhibits Oleic Acid Induced Proliferation and Migration of Rat Vascular Smooth Muscle Cells

BACKGROUND: Oleic acid (OA) stimulates vascular smooth muscle cell (VSMC) proliferation and migration. The precise mechanism is still unclear. We sought to investigate the effects of peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 alpha (PGC-1alpha) on OA-induced VSMC proliferation and migration. PRINCIPAL FINDINGS: Oleate and palmitate, the most abundant monounsaturated fatty acid and saturated fatty acid in plasma, respectively, differently affect the mRNA and protein levels of PGC-1alpha in VSMCs. OA treatment resulted in a reduction of PGC-1alpha expression, which may be responsible for the increase in VSMC proliferation and migration caused by this fatty acid. In fact, overexpression of PGC-1alpha prevented OA-induced VSMC proliferation and migration while suppression of PGC-1alpha by siRNA enhanced the effects of OA. In contrast, palmitic acid (PA) treatment led to opposite effects. This saturated fatty acid induced PGC-1alpha expression and prevented OA-induced VSMC proliferation and migration. Mechanistic study demonstrated that the effects of PGC-1alpha on VSMC proliferation and migration result from its capacity to prevent ERK phosphorylation. CONCLUSIONS: OA and PA regulate PGC-1alpha expression in VSMCs differentially. OA stimulates VSMC proliferation and migration via suppression of PGC-1alpha expression while PA reverses the effects of OA by inducing PGC-1alpha expression. Upregulation of PGC-1alpha in VSMCs provides a potential novel strategy in preventing atherosclerosis

PGC-1α 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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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

Microscopical methods for the localization of Na + , K + -ATPase

Na + , K + -ATPase plays a central role in the ionic and osmotic homeostasis of cells and in the movements of electrolytes and water across epithelial boundaries. Microscopic localization of the enzyme is, therefore, of crucial importance in establishing the subcellular routes of electrolyte flow across structurally complex and functionally polarized epithelia. Recently developed approaches to the localization of Na + , K + -ATPase are reviewed. These methods rely on different properties of the enzyme and encompass cytochemical localization of the K + -dependent nitrophenylphosphatase component of the enzyme, autoradiographic localization of tritiated ouabain binding sites, and immunocytochemical localization of the holoenzyme and of its catalytic subunit. The rationales for each of these techniques are outlined as are the critieria that have been established to validate each method. The observed localization of Na + , K + -ATPase in various tissues is discussed, particularly as it relates to putative and hypothetical mechanisms that are currently thought to mediate reabsorptive and secretory electrolyte transport.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42850/1/10735_2005_Article_BF01005056.pd

Vascular Remodeling in Health and Disease

The term vascular remodeling is commonly used to define the structural changes in blood vessel geometry that occur in response to long-term physiologic alterations in blood flow or in response to vessel wall injury brought about by trauma or underlying cardiovascular diseases.1, 2, 3, 4 The process of remodeling, which begins as an adaptive response to long-term hemodynamic alterations such as elevated shear stress or increased intravascular pressure, may eventually become maladaptive, leading to impaired vascular function. The vascular endothelium, owing to its location lining the lumen of blood vessels, plays a pivotal role in regulation of all aspects of vascular function and homeostasis.5 Thus, not surprisingly, endothelial dysfunction has been recognized as the harbinger of all major cardiovascular diseases such as hypertension, atherosclerosis, and diabetes.6, 7, 8 The endothelium elaborates a variety of substances that influence vascular tone and protect the vessel wall against inflammatory cell adhesion, thrombus formation, and vascular cell proliferation.8, 9, 10 Among the primary biologic mediators emanating from the endothelium is nitric oxide (NO) and the arachidonic acid metabolite prostacyclin [prostaglandin I2 (PGI2)], which exert powerful vasodilatory, antiadhesive, and antiproliferative effects in the vessel wall