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J Nutr Biochem. 2016 Jun;32:73-84. doi: 10.1016/j.jnutbio.2016.01.009. Epub 2016 Mar 10.

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.

Author information

1
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.
2
Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA.
3
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Egypt.
4
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.
5
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.

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.

KEYWORDS:

Arterial injury; Diet-induced obesity; Leptin; Sulforaphane; Vascular smooth muscle cells; p70S6K

PMID:
27142739
PMCID:
PMC4875816
DOI:
10.1016/j.jnutbio.2016.01.009
[Indexed for MEDLINE]
Free PMC Article

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