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

Abstract

Polyphenols are widely regarded to have a wide range of health-promoting qualities, including beneficial effects on cardiovascular disease. Historically, the benefits have been linked to their well-recognized 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 metabolized, 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 in vivo 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.

Linked articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.

Figure 1

Chemical structures of polyphenols of high antioxidant potential, including their bioavailability in plasma, analysed without enzymic conjugation. Data were obtained from Phenol‐Explorer database (www.phenol‐explorer.eu). (H) – C_max data obtained from human studies; (R) – C_max data obtained from animal studies – rats; *presented values correspond to the following glycosides: delphinidin‐3‐O‐rutinoside, cyanidin‐3‐O‐glucoside, peonidin‐3‐O‐glucoside and malvidin‐3‐O‐glucoside; N/A‐ data not available.

Figure 2

Polyphenol classification. Classes of polyphenols with examples that exhibit possible cardioprotective effects.

Figure 3

Indirect antioxidant activity of polyphenols mediated via gene expression – a proposed mechanism. ARE, antioxidant responsive element.

Figure 4

17‐β‐oestradiol and phytoestrogens.

Figure 5

Oestrogen receptor and polyphenols – a proposed mechanism of action, taking into account two main ERs regulatory actions; classical (direct) and tethered pathway.

Figure 6

Proposed anti‐platelet mechanism of action of polyphenols.

Figure 7

Diagram of NfκB pathways, and proposed anti‐inflammatory mechanism of action of polyphenols. CRP, C‐reactive protein; IKK, IκB kinase.