Roland Stocker, PhD

Head, Vascular Biology Division
Victor Chang Cardiac Research Institute
Darlinghurst, New South Wales, Australia

 image of Dr. Roland Stocker
Abstract: Population studies suggest cardiovascular health benefits of consuming fruits and vegetables rich in polyphenolic compounds such as flavonoids. The association between dietary polyphenols and atherosclerosis has been confirmed to some extent by intervention studies with certain polyphenols or food extracts rich in polyphenols, which have shown improvements in cardiovascular risk factors such as vascular function and blood pressure. The mechanisms involved in the bioactivity of dietary polyphenols, or their metabolites, may include in vivo antioxidant activity (free radical scavenging), increase in nitric oxide bioavailability, and/or the induction of protective enzymes. We reported previously that the flavonoid quercetin protects arteries from oxidant-induced endothelial dysfunction and attenuates atherosclerosis in apolipoprotein E gene knockout mice, with induction of heme oxygenase-1 (Hmox1) playing a critical role. The present study investigated the structural requirements of flavonoids to induce Hmox1 in human aortic endothelial cells (HAEC). We identified ortho-dihydroxyl groups and an α, β-unsaturated system attached to a catechol as the key structural requirements for Hmox1 induction. Active but not inactive flavonoids had a low oxidation potential and prevented ascorbate autoxidation, suggesting that Hmox1 inducers readily undergo oxidation and that oxidized, rather than reduced, flavonoids may be the biological inducer of Hmox1. To test this hypothesis, we synthesized stable derivatives of caffeic acid (3-(3,4-dihyroxyphenyl)-2-propenoic acid) containing either ortho-dihydroxy or ortho-dioxo groups. Compared with the dihydroxy compound, the oxidized (quinone) analog induced Hmox1 more potently in HAEC and also provided enhanced protection to arteries of wild type animals against oxidant-induced endothelial dysfunction. In contrast, the quinone analog failed to provide protection against oxidant-induced endothelial dysfunction in arteries of Hmox1–/– mice, establishing a key role for Hmox1 in vascular protection. These results suggest that oxidized forms of dietary polyphenols are the likely inducers of Hmox1 and may explain in part the protective cardiovascular effects of diets rich in these compounds.