Pharmacological basis and new insights of resveratrol action in the cardiovascular system

Abstract

Resveratrol (trans-3,4',5-trihydroxystilbene) belongs to the family of natural phytoalexins. Resveratrol first came to our attention in 1992, following reports of the cardioprotective effects of red wine. Thereafter, resveratrol was shown to exert antioxidant, anti-inflammatory, anti-proliferative, and angio-regulatory effects against atherosclerosis, ischaemia, and cardiomyopathy. This article critically reviews the current findings on the molecular basis of resveratrol-mediated cardiovascular benefits, summarizing the broad effects of resveratrol on longevity regulation, energy metabolism, stress resistance, exercise mimetics, circadian clock, and microbiota composition. In addition, this article also provides an update, both preclinically and clinically, on resveratrol-induced cardiovascular protection and discusses the adverse and inconsistent effects of resveratrol reported in both preclinical and clinical studies. Although resveratrol has been claimed as a master anti-aging agent against several age-associated diseases, further detailed mechanistic investigation is still required to thoroughly unravel the therapeutic value of resveratrol against cardiovascular diseases at different stages of disease development. LINKED ARTICLES: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc.

Figure 1

The cardiovascular benefits of resveratrol. The diagram outlines the six major cardiovascular benefits of resveratrol. Resveratrol exerts its effects in the context of longevity regulation, energy metabolism, stress resistance, exercise mimetic, circadian clock, and microbiota composition. Corresponding positive outcomes are listed

Figure 2

The deacetylating action of resveratrol‐activated SIRT1. (a) SIRT1 deacetylates and hence enhances the activity of eNOS, which also undergoes phosphorylation by AMPK for NO production. SIRT1 deacetylates LKB1 to promote AMPK phosphorylation for downstream eNOS activation. SIRT1 directly activates and may indirectly activate UCP2 through AMPK to counteract oxidative stress. (b) SIRT1 modulates transcriptional activity by directly deacetylating the transcription factors themselves (e.g., NF‐κB and FOXOs), epigenetically acting as a histone deacetylase for transcription factors (e.g., KLF2), indirectly deacetylating the co‐activator of the transcription factor complex (e.g., PPARs) or the combination of above mechanisms (e.g., CLOCK:BMAL1)

Figure 3

Common endothelial benefits induced by laminar shear stress and resveratrol. Both shear stress and resveratrol trigger SIRT1 up‐regulation, ROS level down‐regulation, inhibition of monocyte recruitment, increased autophagy, endothelial elongation, and improved re‐endothelialization in endothelial cells. Similar elongation patterns are observed in phase contrast images of laminar flow‐treated (reproduced with permission; Copyright 2017, Development; Poduri et al., 2017) and resveratrol‐treated endothelial cells (reproduced with permission; Copyright 2011, Journal of Atherosclerosis and Thrombosis; Cicha et al., 2011)