Resveratrol prevents endothelial dysfunction and aortic superoxide production after trauma hemorrhage through estrogen receptor-dependent hemeoxygenase-1 pathway.

Abstract

To determine whether resveratrol provides vasculoprotection in trauma-hemorrhaged animals and whether the effects are mediated via estrogen receptor-dependent hemeoxygenase-1. Prospective, multiexperimental, randomized, controlled studies. University research laboratory. Male Sprague-Dawley rats weighing 300-350 g. Male Sprague-Dawley rats underwent trauma hemorrhage (mean arterial pressure 40 mm Hg for 90 min, then resuscitation). Resveratrol (30 mg/kg) with or without an estrogen receptor antagonist (ICI 182,780), a hemeoxygenase enzyme inhibitor (chromium-mesoporphyrin), or vehicle was injected during resuscitation. At 24 hrs after trauma hemorrhage with resuscitation or sham operation, the animals were euthanized for further evaluation. Acetylcholine-induced endothelium-dependent relaxation decreased, whereas nicotinamide adenine dinucleotide-stimulated superoxide radical production in the aorta and aortic p22phox, p47phox, gp91phox, NOX1, and NOX4 mRNA concentrations increased in trauma-hemorrhaged rats vs. sham rats. All altered parameters were normalized in resveratrol-treated trauma-hemorrhaged rats. Furthermore, there was a significant increase in hemeoxygenase-1 after trauma hemorrhage, and resveratrol treatment further increased hemeoxygenase-1 expression in trauma-hemorrhaged rats. However, administration of ICI 182,780 or chromium-mesoporphyrin abolished the resveratrol-induced prevention of shock-induced oxidative stress and endothelial damage. In the resveratrol-treated rats subjected to trauma hemorrhage, there were significant improvements in plasma aspartate aminotransferase and alanine aminotransferase levels, and mortality rate, and there was lesser damage in histology. Resveratrol treatment prevented the overproduction of superoxide radical/NADPH oxidase expression and restored the trauma-hemorrhage-impaired endothelium-dependent relaxation via estrogen receptor-dependent stimulation of hemeoxygenase-1 expression.