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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • 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
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Diet, Western / adverse effects
  • Femoral Artery / injuries
  • Humans
  • Injections, Subcutaneous
  • Insulin Resistance
  • Isothiocyanates / administration & dosage
  • Isothiocyanates / pharmacology
  • Isothiocyanates / therapeutic use*
  • 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
  • Weight Gain / drug effects

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Anti-Obesity Agents
  • Anticarcinogenic Agents
  • Antioxidants
  • Isothiocyanates
  • Leptin
  • sulforafan