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Cross‐talk of Leptin and TSP‐1 in Leptin‐induced Atherosclerosis
Author(s) -
Sahu Soumyadip,
Ganguly Rituparna,
Raman Priya
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.638.6
Subject(s) - leptin , medicine , endocrinology , apolipoprotein e , in vivo , chemistry , cholesterol , biology , obesity , microbiology and biotechnology , disease
Hyperleptinemia is an important pathogenic contributor of atherosclerosis; however, underlying mechanisms are poorly understood. We reported earlier that leptin upregulates a potent proatherogenic protein, thrombospondin‐1 (TSP‐1), in human aortic smooth muscle cells (HASMC) in vitro and aortic vessels of C57BL/6J mice in vivo . The goal of the current study was to determine the molecular mechanisms by which leptin upregulates TSP‐1 and further delineate the role of TSP‐1 in leptin‐induced atherosclerosis. Using ChIP, we found that leptin in vitro enhanced recruitment of nuclear proteins IRF1 and CREB on TSP‐1 gene promoter in HASMC. Immunoblotting further revealed that leptin in vivo , at doses reported to increase TSP‐1, stimulated IRF1 expression in aortic lysates of WT mice vs. untreated controls; in contrast, leptin failed to increase IRF1 expression in aortic vessels of TSP‐1 ‐/‐ mice. Finally, to elucidate a direct role of TSP‐1 in leptin‐induced atherosclerosis, age‐matched ApoE ‐/‐ and TSP‐1 ‐/‐ /ApoE ‐/‐ mice on regular chow at 17 wks of age were treated once daily i.p. with leptin (5µg/g) for 3 wks. While leptin‐treated TSP‐1 ‐/‐ /ApoE ‐/‐ had lower plasma cholesterol levels compared to leptin‐treated ApoE ‐/‐ mice, FPLC fractionation of plasma lipids indicated that this difference was not attributable to VLDL and LDL levels. Morphometry of aortic root demonstrated a significant increase in atherosclerotic lesion area, collagen content and PCNA expression (proliferation marker) in ApoE ‐/‐ vs. TSP‐1 ‐/‐ /ApoE ‐/‐ mice in response to leptin, suggesting that TSP‐1 deletion protects against leptin‐induced atherosclerosis. Overall, our data suggest a potential cross‐talk between leptin and TSP‐1 that may play a critical role in hyperleptinemia‐induced atherosclerosis.