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

Ronaldo J. Chavez, Rebecca M. Haney, Rene H. Cuadra, Rituparna Ganguly, Ravi K. Adapala, Charles K. Thodeti, Priya Raman
2012 American Journal of Physiology - Cell Physiology  
Chavez RJ, Haney RM, Cuadra RH, Ganguly R, Adapala RK, Thodeti CK, Raman P. Upregulation of thrombospondin-1 expression by leptin in vascular smooth muscle cells via JAK2-and MAPKdependent pathways. Hyperleptinemia, characteristic of diabetes and a hallmark feature of human obesity, contributes to the increased risk of atherosclerotic complications. However, molecular mechanisms mediating leptininduced atherogenesis and gene expression in vascular cells remain incompletely understood.
more » ... ng 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/JNKdependent 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 leptinmediated 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. leptin; thrombospondin-1; vascular smooth muscle cell; Janus kinase 2; mitogen-activated protein kinase
doi:10.1152/ajpcell.00008.2012 pmid:22592401 fatcat:zaspdkbqnzflhney4ofb67gyzm