title: Upregulation of thrombospondin-1 expression by leptin in vascular smooth muscle cells via JAK2- and MAPK-dependent pathways.
abstract: 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.
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272-0095, USA.
authors.forename: Ronaldo J
authors.initials: RJ
authors.lastname: Chavez
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Haney
authors.forename: Rene H
authors.initials: RH
authors.lastname: Cuadra
authors.forename: Rituparna
authors.initials: R
authors.lastname: Ganguly
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Adapala
authors.forename: Charles K
authors.initials: CK
authors.lastname: Thodeti
authors.forename: Priya
authors.initials: P
authors.lastname: Raman
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D053614:Janus Kinase 2 / Q000096:biosynthesis*; D020738:Leptin / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000378:metabolism; D019700:Thrombospondin 1 / Q000096:biosynthesis*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D020738:Leptin; D019700:Thrombospondin 1; C507924:JAK2 protein, human; D053614:Janus Kinase 2