Bioactive polyphenols and cardiovascular disease: chemical antagonists, pharmacological agents or xenobiotics that drive an adaptive response?

Polyphenols are widely regarded to have a wide range of health-promoting qualities, including in the sphere of cardiovascular disease. Historically, the benefits have been linked to their well-recognised powerful antioxidant activity. However, the concept that the beneficial effects are attributable to direct antioxidant activity in vivo does not pay sufficient heed to the fact that polyphenols degrade rapidly, are poorly absorbed and rapidly metabolised, resulting in very low bioavailability. This review explores alternative mechanisms by which polyphenols, or their metabolites, exert biological activity via mechanisms that can be activated by physiologically relevant concentrations. Evidence is presented to support the action of phenolic derivatives on receptors and signalling pathways to induce adaptive responses that drive changes in endogenous antioxidant, antiplatelet, vasodilatory and anti-inflammatory effects. The implications are that in vitro antioxidant measures as predictors of polyphenol protective activity hold little relevance and that closer attention needs to be paid to bioavailable metabolites to understand the mode of action of these diet-derived components.