TSP-1 (Thrombospondin-1) Deficiency Protects ApoE

OBJECTIVE –: Hyperleptinemia, hallmark of obesity, is a putative pathophysiologic trigger for atherosclerosis. We previously reported a stimulatory effect of leptin on thrombospondin-1 (TSP-1) expression, a proatherogenic matricellular protein implicated in atherogenesis. However, a causal role of TSP-1 in leptin-driven atherosclerosis remains unknown. APPROACH AND RESULTS –: 17-wks-old ApoE(−/−) and TSP-1(−/−)/ApoE(−/−) double knockout (dKO) mice, on normocholesterolemic diet, were treated with or without murine recombinant leptin (5µg/g bwt, IP) once daily for three weeks. Using aortic root morphometry and en-face lesion assay, we found that TSP-1 deletion abrogated leptin-stimulated lipid-filled lesion burden, plaque area and collagen accumulation in aortic roots of ApoE(−/−) mice, shown via Oil red O, H & E and Masson’s trichrome staining, respectively. Immunofluorescence microscopy of aortic roots showed that TSP-1 deficiency blocked leptin-induced inflammatory and smooth muscle cell abundance as well as cellular proliferation in ApoE(−/−) mice. Moreover, these effects were concomitant to changes in VLDL-triglyceride and HDL-cholesterol levels. Immunoblotting further revealed reduced vimentin and pCREB accompanied with augmented SM-MHC expression in aortic vessels of leptin-treated dKO vs. leptin-treated ApoE(−/−); also confirmed in aortic SMCs from the mice genotypes, incubated ± leptin in vitro. Finally, TSP-1 deletion impeded plaque burden in leptin-treated ApoE(−/−) on western diet, independent of plasma lipid alterations. CONCLUSIONS –: The present study provides evidence for a protective effect of TSP-1 deletion on leptin-stimulated atherogenesis. Our findings suggest a regulatory role of TSP-1 on leptin-induced VSMC phenotypic transition and inflammatory lesion invasion. Collectively, these results underscore TSP-1 as a potential target of leptin-induced vasculopathy.