| First Author | Ganguly R | Year | 2021 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 41 |
| Issue | 2 | Pages | e112-e127 |
| PubMed ID | 33327743 | Mgi Jnum | J:318574 |
| Mgi Id | MGI:6860285 | Doi | 10.1161/ATVBAHA.120.314962 |
| Citation | Ganguly R, et al. (2021) TSP-1 (Thrombospondin-1) Deficiency Protects ApoE(-/-) Mice Against Leptin-Induced Atherosclerosis. Arterioscler Thromb Vasc Biol 41(2):e112-e127 |
| abstractText | OBJECTIVE: Hyperleptinemia, hallmark of obesity, is a putative pathophysiologic trigger for atherosclerosis. We previously reported a stimulatory effect of leptin on TSP-1 (thrombospondin-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: Seventeen-weeks-old ApoE(-/-) and TSP-1(-/-)/ApoE(-/-) double knockout mice, on normocholesterolemic diet, were treated with or without murine recombinant leptin (5 microg/g bwt, IP) once daily for 3 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, hematoxylin and eosin, and Masson 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 (very low-density lipoprotein)-triglyceride and HDL (high-density lipoprotein)-cholesterol levels. Immunoblotting further revealed reduced vimentin and pCREB (phospho-cyclic AMP response element-binding protein) accompanied with augmented smooth muscle-myosin heavy chain expression in aortic vessels of leptin-treated double knockout versus leptin-treated ApoE(-/-); also confirmed in aortic smooth muscle cells 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 vascular smooth muscle cell phenotypic transition and inflammatory lesion invasion. Collectively, these results underscore TSP-1 as a potential target of leptin-induced vasculopathy. |
