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Signaling Pathways Involved in Human Vascular Smooth Muscle Cell Proliferation and Matrix Metalloproteinase-2 Expression Induced by Leptin

Inhibitory Effect of Metformin

¹ CHUM Research Centre, Vascular Immunology Laboratory, Department of Medicine, Notre-Dame Hospital, University of Montreal, Quebec, Canada
² INSERM U585, INSA Lyon, Batiment L. Pasteur, Villeurbanne, France

Accumulating evidence suggests that high concentrations of leptin observed in obesity and diabetes may contribute to their adverse effects on cardiovascular health. Metformin monotherapy is associated with reduced macrovascular complications in overweight patients with type 2 diabetes. It is uncertain whether such improvement in the cardiovascular outcome is related to specific vasculoprotective effects of this drug. In the present study, we determined the effect of leptin on human aortic smooth muscle cell (HASMC) proliferation and matrix metalloproteinase (MMP)-2 expression, the signaling pathways mediating these effects, and the modulatory effect of metformin on these parameters. Incubation of HASMCs with leptin enhanced the proliferation and MMP-2 expression in these cells and increased the generation of intracellular reactive oxygen species (ROS). These effects were abolished by vitamin E. Inhibition of NAD(P)H oxidase and protein kinase C (PKC) suppressed the effect of leptin on ROS production. In HASMCs, leptin induced PKC, extracellular signal–regulated kinase (ERK)1/2, and nuclear factor-B (NF-B) activation and inhibition of these signaling pathways abrogated HASMC proliferation and MMP-2 expression induced by this hormone. Treatment of HASMCs with metformin decreased leptin-induced ROS production and activation of PKC, ERK1/2, and NF-B. Metformin also inhibited the effect of leptin on HASMC proliferation and MMP-2 expression. Overall, these results demonstrate that leptin induced HASMC proliferation and MMP-2 expression through a PKC-dependent activation of NAD(P)H oxidase with subsequent activation of the ERK1/2/NF-B pathways and that therapeutic metformin concentrations effectively inhibit these biological effects. These results suggest a new mechanism by which metformin may improve cardiovascular outcome in patients with diabetes.

Abbreviations: AMPK, AMP kinase; DCF-DA, 2',7'-dichlorodihydrofluorescein diacetate; DPI, diphenyleneiodonium; ELISA, enzyme-linked immunosorbent assay; ERK, extracellular signal–regulated kinase; FBS, fetal bovine serum; HASMC, human aortic smooth muscle cell; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; MTT, 3-(4,5-dimethylthiazol-2-yl)-5-diphenyltetrazolium bromide; NF-B, nuclear factor-B; PKC, protein kinase C; ROS, reactive oxygen species; TTFA, thenoyltrifluoroacetone

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