期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 41, 期 2, 页码 E112-E127出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.120.314962
关键词
atherosclerosis; leptin; obesity; smooth muscle; thrombospondins
资金
- American Heart Association Scientist Development [0835190N]
- Diabetes Action Research and Education Foundation [1R15HL147245-01]
- Northeast Ohio Medical University (NEOMED) start-up funds
The study demonstrates a protective effect of TSP-1 deletion on leptin-stimulated atherogenesis, indicating a regulatory role of TSP-1 on leptin-induced vascular smooth muscle cell phenotypic transition and inflammatory lesion invasion. These results highlight TSP-1 as a potential target for leptin-induced vasculopathy.
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 mu g/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.
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