Sulforaphane improves dysregulated metabolic profile and inhibits leptin-induced VSMC proliferation: Implications toward suppression of neointima formation after arterial injury in western diet-fed obese mice

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• 作者：Noha M. Shawky^a ; ^b ; ^c ; Prahalathan Pichavaram^a ; ^b ; George S.G. Shehatou^c ; Ghada M. Suddek^c ; Nariman M. Gameil^c ; John Y. Jun^d ; ^e ; Lakshman Segar^a ; ^b ; ^e ; ^f ; ^{lsegar@gru.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Sulforaphane ; Diet-induced obesity ; Arterial injury ; Vascular smooth muscle cells ; Leptin ; p70S6K
• 刊名：Journal of Nutritional Biochemistry
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：32
• 期：Complete
• 页码：73-84
• 全文大小：2001 K

文摘

Sulforaphane (SFN), a dietary phase-2 enzyme inducer that mitigates cellular oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2) activation, is known to exhibit beneficial effects in the vessel wall. For instance, it inhibits vascular smooth muscle cell (VSMC) proliferation, a major event in atherosclerosis and restenosis after angioplasty. In particular, SFN attenuates the mitogenic and pro-inflammatory actions of platelet-derived growth factor (PDGF) and tumor necrosis factor-α (TNFα), respectively, in VSMCs. Nevertheless, the vasoprotective role of SFN has not been examined in the setting of obesity characterized by hyperleptinemia and insulin resistance. Using the mouse model of western diet-induced obesity, the present study demonstrates for the first time that subcutaneous delivery of SFN (0.5 mg/Kg/day) for ~ 3 weeks significantly attenuates neointima formation in the injured femoral artery [↓ (decrease) neointima/media ratio by ~ 60%; n = 5–8]. This was associated with significant improvements in metabolic parameters, including ↓ weight gain by ~ 52%, ↓ plasma leptin by ~ 42%, ↓ plasma insulin by ~ 63%, insulin resistance [↓ homeostasis model assessment of insulin resistance (HOMA-IR) index by ~ 73%], glucose tolerance (↓ AUC_GTT by ~ 24%), and plasma lipid profile (e.g., ↓ triglycerides). Under in vitro conditions, SFN significantly decreased leptin-induced VSMC proliferation by ~ 23% (n = 5) with associated diminutions in leptin-induced cyclin D1 expression and the phosphorylation of p70S6kinase and ribosomal S6 protein (n = 3–4). The present findings reveal that, in addition to improving systemic metabolic parameters, SFN inhibits leptin-induced VSMC proliferative signaling that may contribute in part to the suppression of injury-induced neointima formation in diet-induced obesity.