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

• Published in: The Journal of nutritional biochemistry Vol. 32; pp. 73 - 84
• Main Authors: Shawky, Noha M., Pichavaram, Prahalathan, Shehatou, George S.G., Suddek, Ghada M., Gameil, Nariman M., Jun, John Y., Segar, Lakshman
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2016
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Anti-Obesity Agents - administration & dosage; Anti-Obesity Agents - pharmacology; Anti-Obesity Agents - therapeutic use; Anticarcinogenic Agents - administration & dosage; Anticarcinogenic Agents - pharmacology; Anticarcinogenic Agents - therapeutic use; Antioxidants - administration & dosage; Antioxidants - pharmacology; Antioxidants - therapeutic use; Aorta; Arterial injury; Cell Proliferation - drug effects; Cells, Cultured; Diet, Western - adverse effects; Diet-induced obesity; Femoral Artery - injuries; Humans; Injections, Subcutaneous; Insulin Resistance; Isothiocyanates - administration & dosage; Isothiocyanates - pharmacology; Isothiocyanates - therapeutic use; Leptin; Leptin - antagonists & inhibitors; Leptin - metabolism; Male; Mice, Inbred C57BL; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - immunology; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Neointima - immunology; Neointima - metabolism; Neointima - pathology; Neointima - prevention & control; Obesity - drug therapy; Obesity - immunology; Obesity - metabolism; Obesity - pathology; Oxidative Stress - drug effects; p70S6K; Sulforaphane; Vascular smooth muscle cells; Weight Gain - drug effects; Diet-induced obesity; p70S6K; Arterial injury; Sulforaphane; Leptin; Vascular smooth muscle cells
• ISSN: 0955-2863; 1873-4847
• DOI: 10.1016/j.jnutbio.2016.01.009

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 (0.5mg/Kg/day) for~3weeks 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 (↓ AUCGTT 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. Effects of SFN on dysregulated metabolic parameters and injury-induced neointima formation in western diet (HFHS)-fed obese C57BL/6J mice. SFN treatment attenuates weight gain and eWAT weight and improves systemic metabolic abnormalities (e.g., ↓ plasma leptin and insulin, improves HOMA-IR and glucose tolerance, and lowers plasma triglycerides/FFA and systolic blood pressure). In addition, SFN suppresses injury-induced intimal hyperplasia in the femoral artery and inhibits leptininduced VSMC proliferation by targeting p70S6K/S6 signaling. The use of SFN as a dietary supplement may provide a rational prophylactic approach to target restenosis after angioplasty in diet-induced obesity. [Display omitted]