Potential Protective Effects of Equol (Soy Isoflavone Metabolite) on Coronary Heart Diseases-From Molecular Mechanisms to Studies in Humans

Abstract

Equol, a soy isoflavone-derived metabolite of the gut microbiome, may be the key cardioprotective component of soy isoflavones. Systematic reviews have reported that soy isoflavones have no to very small effects on traditional cardiovascular disease risk factors. However, the potential mechanistic mode of action of equol on non-traditional cardiovascular risk factors has not been systematically reviewed. We searched the PubMed through to July 2021 by using terms for equol and each of the following markers: inflammation, oxidation, endothelial function, vasodilation, atherosclerosis, arterial stiffness, and coronary heart disease. Of the 231 records identified, 69 articles met the inclusion criteria and were summarized. Our review suggests that equol is more lipophilic, bioavailable, and generally more potent compared to soy isoflavones. Cell culture, animal, and human studies show that equol possesses antioxidative, anti-inflammatory, and vasodilatory properties and improves arterial stiffness and atherosclerosis. Many of these actions are mediated through the estrogen receptor β. Overall, equol may have a greater cardioprotective benefit than soy isoflavones. Clinical studies of equol are warranted because equol is available as a dietary supplement.

Keywords: arterial stiffness; atherosclerosis; coronary heart disease; endothelial function; equol; flavonoid; inflammation; isoflavones; lipophilicity; oxidation.

Figure 1

Search strategies in PubMed (inception to 28 July 2021) and the literature selection process.

Figure 2

Structures of genistein, daidzein, and equol [48,49,50]. Genistein and daidzein are two major ISFs and comprise >95% of dietary sources. Equol is a metabolite of daidzein, biotransformed by gut bacteria.

Figure 3

Signaling and pathways in which equol exerts anti-inflammatory effects. (A): PGE2 pathway [61]. (B): TNF-α [62] and IL-1 pathway [69]. (C): TLR4 [65] and IL-6 pathway [69]. (D): MCP-1 pathway [64]. “⏊” indicates the inhibitory effect by equol. PGE2: prostaglandin E2, cAMP: cyclic adenosine monophosphate, PKA: protein kinase A, IL: interleukin, TNF: tumor necrosis factor, iNOS: nitric oxide system, TNFR: TNF receptor, TRADD: TNFR1-associated death domain protein, TRAF2: TNF receptor-associated factor 2, PI3K or Akt: phosphoinositide 3-kinases, MAPK or P38: mitogen-activated protein kinase, AP: activator protein, NF-kB: nuclear factor kappa B, ICAM: intercellular adhesion molecule, VCAM: vascular cell adhesion molecule, IL-R: interleukin receptor, LPS: lipopolysaccharide, TLR: Toll-like receptor, TRIF: Toll/IL-1R domain-containing adaptor-inducing IFN-β, TRAM: TRIF-related adaptor molecule, TRAF: TNFR-associated factor, RIP: receptor-interacting protein, IRF: IFN regulatory factor, IFN: interferon, JAK: janus kinase, SHP: Src homology-2 domain-containing protein tyrosine phosphatase, AR: androgen receptor, MCP: monocyte chemoattractant protein, CCR: Chemokine receptor, MCPIP: monocyte chemoattractant protein-induced protein.

Figure 4

Signaling and pathways on which equol exerts antioxidative effect. (A): ROS pathway [99]. (B): NADPH pathway [91]. “⏊” indicates the inhibitory effect by equol. MDA: malondialdehyde, 4-HNE: dyhidroxynonel, LOOHs: lipid hydroperoxides, ROS: reactive oxygen, DNA: deoxyribonucleic acid, ONOO-: peroxynitrite, NO₂: nitrogen dioxide, O₂-: superoxide, MPO: myeloperoxidase, NADPH: nicotinamide adenine dinucleotide phosphate, apoB: apolipoprotein B, iNOS: inducible nitric oxide synthase, H₂O₂: hydrogen peroxide.