title: 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.
abstract: 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.
authors.affiliation: Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Egypt.
authors.forename: Noha M
authors.initials: NM
authors.lastname: Shawky
authors.affiliation: Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Prahalathan
authors.initials: P
authors.lastname: Pichavaram
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Egypt.
authors.forename: George S G
authors.initials: GS
authors.lastname: Shehatou
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Egypt.
authors.forename: Ghada M
authors.initials: GM
authors.lastname: Suddek
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Egypt.
authors.forename: Nariman M
authors.initials: NM
authors.lastname: Gameil
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Pennsylvania State University College of Medicine, Hershey, PA, USA; Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA.
authors.forename: John Y
authors.initials: JY
authors.lastname: Jun
authors.affiliation: Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA; Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA; Vascular Biology Center, Department of Pharmacology and Toxicology, Augusta University, Augusta, GA, USA. Electronic address: lsegar@gru.edu.
authors.forename: Lakshman
authors.initials: L
authors.lastname: Segar
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001011:Aorta; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D066273:Diet, Western / Q000009:adverse effects; D005263:Femoral Artery / Q000293:injuries; D006801:Humans; D007279:Injections, Subcutaneous; D007333:Insulin Resistance; D017879:Isothiocyanates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020738:Leptin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058426:Neointima / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009765:Obesity / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D013454:Sulfoxides; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D019440:Anti-Obesity Agents; D016588:Anticarcinogenic Agents; D000975:Antioxidants; D017879:Isothiocyanates; D020738:Leptin; D013454:Sulfoxides; C016766:sulforaphane
keywords: Arterial injury; Diet-induced obesity; Leptin; Sulforaphane; Vascular smooth muscle cells; p70S6K