Upregulation of thrombospondin-1 expression by leptin in vascular smooth muscle cells via JAK2- and MAPK-dependent pathways.

Upregulation of thrombospondin-1 expression by leptin in vascular smooth muscle cells via JAK2- and MAPK-dependent pathways.

Chavez Ronaldo J; Haney Rebecca M; Cuadra Rene H; Ganguly Rituparna; Adapala Ravi K; Thodeti Charles K; Raman Priya

American journal of physiology. Cell physiology

2012

2012-07

Hyperleptinemia, characteristic of diabetes and a hallmark feature of human obesity, contributes to the increased risk of atherosclerotic complications. However, molecular mechanisms mediating leptin-induced atherogenesis and gene expression in vascular cells remain incompletely understood. Accumulating evidence documents a critical role of a potent antiangiogenic and proatherogenic matricellular protein, thrombospondin-1 (TSP-1), in atherosclerosis. Although previous studies reported elevated TSP-1 levels in both diabetic and obese patients and rodent models, there is no direct information on TSP-1 expression in vascular cells in response to leptin. In the present study, we show that leptin upregulates TSP-1 expression in cultured human aortic smooth muscle cells (HASMC) in vitro, and this increase occurs at the level of transcription, revealed by mRNA stability and TSP-1 promoter-reporter assays. Utilizing specific pharmacological inhibitors and siRNA approaches, we demonstrate that upregulation of TSP-1 expression by leptin is mediated by JAK2/ERK/JNK-dependent mechanisms. Furthermore, we report that while ERK and JNK are required for both the constitutive and leptin-induced expression of TSP-1, JAK-2 appears to be specifically involved in leptin-mediated TSP-1 upregulation. Finally, we found that increased HASMC migration and proliferation in response to leptin is significantly inhibited by a TSP-1 blocking antibody, thereby revealing the physiological significance of leptin-TSP-1 crosstalk. Taken together, these findings demonstrate, for the first time, that leptin has a direct regulatory effect on TSP-1 expression in HASMCs, underscoring a novel role of TSP-1 in hyperleptinemia-induced atherosclerotic complications.

Animals; Cell Movement/physiology; Cells; Cultured; Gene Expression Regulation/physiology; Humans; Inbred C57BL; Janus Kinase 2/*biosynthesis; Knockout; Leptin/*physiology; Male; MAP Kinase Signaling System/*physiology; Mice; Muscle; Myocytes; Smooth; Smooth Muscle/enzymology/metabolism; Thrombospondin 1/*biosynthesis; Up-Regulation/*physiology; Vascular/enzymology/*metabolism

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