TSP-1 (thrombospondin-1) deficiency protects APOE(-/-) mice against leptin-induced atherosclerosis.

Title

TSP-1 (thrombospondin-1) deficiency protects APOE(-/-) mice against leptin-induced atherosclerosis.

Creator

Ganguly R; Khanal S; Mathias A; Gupta S; Lallo J; Sahu S; Ohanyan VA; Patel A; Storm K; Datta S; Raman P

Publisher

Arteriosclerosis, Thrombosis, and Vascular Biology

Date

2020
2020-12-17

Description

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 µg/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 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.

Subject

atherosclerosis; leptin; obesity; smooth muscle; thrombospondins

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Format

journalArticle

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Pages

ATVBAHA120314962

ISSN

1524-4636 1079-5642

NEOMED College

NEOMED College of Medicine

NEOMED Department

Department of Integrative Medical Sciences

Update Year & Number

January 2021 List

Citation

Ganguly R; Khanal S; Mathias A; Gupta S; Lallo J; Sahu S; Ohanyan VA; Patel A; Storm K; Datta S; Raman P, “TSP-1 (thrombospondin-1) deficiency protects APOE(-/-) mice against leptin-induced atherosclerosis.,” NEOMED Bibliography Database, accessed April 13, 2021, https://neomed.omeka.net/items/show/11506.

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