Upregulation of thrombospondin‐1 expression by leptin in vascular smooth muscle cells: role of MAPK, JAK2 and PKC signaling pathways

Leptin (an adipose tissue‐secreted peptide) and thrombospondin‐1 (TSP‐1, a potent proatherogenic matricellular protein) are both linked to accelerated atherosclerotic lesion formation and progression. However, nothing is known about direct effects of leptin on TSP‐1 in the vasculature. The goal of this study was to explore the regulatory effects of leptin on TSP‐1 in vascular walls of mice and human aortic smooth muscle cells (HASMC). Leptin in vivo increased TSP‐1 expression in aortic vessel walls of C57BL/6 mice. Consistently, there was a significant increase in TSP‐1 mRNA and protein expression in HASMC stimulated with leptin in vitro . Using mRNA stability and transient transfection studies with TSP‐1 promoter‐reporter construct, we observed that leptin activates TSP‐1 gene at the level of transcription. Pretreatment of HASMC with MAPK, JAK2 and PKC‐specific inhibitors significantly attenuated leptin‐induced increase in TSP‐1 mRNA, protein expression (59%–87%) and TSP‐1 promoter activity (32%–52%). Finally, using TSP‐1 blocking antibodies, we demonstrated that leptin‐induced increase in HASMC migration and proliferation was mediated via TSP‐1. Taken together, these data suggest that leptin modulates VSMC function through upregulation of TSP‐1 via MAPK, JAK2 and PKC‐dependent pathways, which may play a potential role in leptin‐induced atherosclerotic complications. Supported by AHA‐SDG