Omega-3 Polyunsaturated Fatty Acids Protect Against Cigarette Smoke-Induced Oxidative Stress and Vascular Dysfunction

Toxicol Sci. 2017 Mar 1;156(1):300-310. doi: 10.1093/toxsci/kfw255.

Abstract

In cigarette smokers endothelial dysfunction, measured by flow-mediated dilation (FMD), precedes cardiovascular disease (CVD) and can be improved by supplementation with n - 3 polyunsaturated fatty acids (PUFAs). We developed a mouse model of cigarette smoke (CS)-induced endothelial dysfunction that resembles impaired FMD observed in human cigarette smokers and investigated the mechanism by which n - 3 PUFAs mediate vasoprotection. We hypothesized that loss of nitric oxide (NO)-dependent vasodilation in CS-exposed mice would be prevented by dietary n - 3 PUFAs via a decrease in oxidative stress. C57BL/6 mice were fed a chow or n - 3 PUFA diet for 8 weeks and then exposed to mainstream CS or filtered air for 5 days, 2 h/day. Mesenteric arterioles were preconstricted with U46619 and dilated by stepwise increases in pressure (0-40 mmHg), resulting in increases in flow, ± inhibitor of NO production or antioxidant, Tempol. Markers of oxidative stress were measured in lung and heart. CS-exposed mice on a chow diet had impaired FMD, resulting from loss of NO-dependent dilation, compared with air exposed mice. Tempol restored FMD by normalizing NO-dependent dilation and increasing NO-independent dilation. CS-exposed mice on the n - 3 PUFA diet had normal FMD, resulting from a significant increase in NO-independent dilation, compared with CS-exposed mice on a chow diet. Furthermore, n - 3 PUFAs decreased two CS-induced markers of oxidative stress, 8-epiprostaglandin-F2α levels and heme oxygenase-1 mRNA, and significantly attenuated CS-induced cytochrome P4501A1 mRNA expression. These data demonstrate that dietary n - 3 PUFAs can protect against CS-induced vascular dysfunction via multiple mechanisms, including increasing NO-independent vasodilation and decreasing oxidative stress.

Keywords: cigarette smoke; flow-mediated dilation; omega-3 polyunsaturated fatty acids; oxidative stress; vasodilation..

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Arterioles / drug effects
  • Arterioles / metabolism
  • Arterioles / physiopathology
  • Atmosphere Exposure Chambers
  • Biomarkers / blood
  • Biomarkers / metabolism
  • Biomarkers / urine
  • Cardiovascular Agents / blood
  • Cardiovascular Agents / metabolism
  • Cardiovascular Agents / therapeutic use*
  • Cigarette Smoking / adverse effects*
  • Dietary Supplements*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / physiopathology*
  • Fatty Acids, Omega-3 / blood
  • Fatty Acids, Omega-3 / metabolism
  • Fatty Acids, Omega-3 / therapeutic use*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Heart Ventricles / drug effects
  • Heart Ventricles / metabolism
  • Lung / drug effects
  • Lung / metabolism
  • Male
  • Mesenteric Arteries / drug effects
  • Mesenteric Arteries / metabolism
  • Mesenteric Arteries / physiopathology
  • Mice, Inbred C57BL
  • Oxidative Stress* / drug effects
  • Random Allocation
  • Smoke / adverse effects
  • Vascular Diseases / etiology
  • Vascular Diseases / metabolism
  • Vascular Diseases / physiopathology
  • Vascular Diseases / prevention & control*
  • Vascular Resistance / drug effects
  • Vasodilation / drug effects

Substances

  • Antioxidants
  • Biomarkers
  • Cardiovascular Agents
  • Fatty Acids, Omega-3
  • Smoke