Soy-Derived Isoflavones Exert Opposing Actions on Guinea Pig Ventricular Myocytes

Abstract

Soy-derived isoflavones appear to possess cardioprotective properties, although the precise nature of this protection and the particular isoflavones responsible remain unclear. We hypothesized that isoflavones may differ in their cardiac actions in view of their varying affinities for the estrogen receptor and differences in ability to inhibit tyrosine kinase. We investigated the direct effects of three closely related isoflavones, genistein, daidzein, and equol (a metabolite of daidzein formed by gut microflora), on the contractile function of isolated guinea pig ventricular myocytes. Genistein (10 and 40 M) significantly increased cell shortening and the Ca 2ϩ transient (measured using indo-1). In contrast, equivalent concentrations of equol produced the opposite effect, decreasing cell shortening and the Ca 2ϩ transient, whereas daidzein was without effect. The opposing actions of genistein and equol were still observed in the presence of the specific estrogen receptor antagonist ICI 182,780 (10 M). However, the stimulatory actions of genistein were markedly reduced in the presence of the potent phosphotyrosine phosphatase inhibitor, bpV(phen). Both genistein and equol significantly inhibited the peak L-type Ca 2ϩ current. We conclude that genistein and equol affect the contractile function of ventricular myocytes in opposing ways despite a common initial action of Ca 2ϩ current antagonism. These differences occur independently of the estrogen receptor but may be partly related to the unique actions of genistein as a tyrosine kinase inhibitor. Furthermore, isoflavone metabolites, such as equol, may be more biologically active than their precursors and have a greater role in cardioprotection than previously realized.

Dietary isoflavones during pregnancy and lactation provide cardioprotection to offspring rats in adulthood

“…However, most of the effects of these compounds have been attributed to exposure during adult life, and they have not previously been shown to have enduring structural effects. Likewise, isoflavones have been reported to inhibit L-type Ca 2ϩ current in cultured cardiomyocytes (27), but such direct actions in vitro are clearly of a different nature than the effects observed in the present study. Of note, genistein (but not daidzein or its metabolites) has anti-tyrosine kinase properties (27), and daidzein (but not genistein) can be metabolized by intestinal flora into the bioactive metabolite equol (2).…”

“…Likewise, isoflavones have been reported to inhibit L-type Ca 2ϩ current in cultured cardiomyocytes (27), but such direct actions in vitro are clearly of a different nature than the effects observed in the present study. Of note, genistein (but not daidzein or its metabolites) has anti-tyrosine kinase properties (27), and daidzein (but not genistein) can be metabolized by intestinal flora into the bioactive metabolite equol (2). However, the equivalent potency of both compounds indicates that their effects on the length of CMs cannot be attributed solely to inhibition of tyrosine kinases or intestinal metabolism.…”

The Soybean Isoflavonoid Equol Blocks Ritonavir-Induced Endothelial Dysfunction in Porcine Pulmonary Arteries and Human Pulmonary Artery Endothelial Cells

“…Equol also has a longer plasma half-life than its parent compound, daidzein; it is detected in the urine for longer following soy challenge (20). It is also more biologically active than daidzein in enhancing cardiac cell function (21) and has more antioxidant effects in arterial segments in vivo and in vitro (22). As such, equol has been predicted to provide more cardiovascular protection than its parent compound daidzein (23); together with the aforementioned variation in gut production in individuals, there is a shift to focus on using equol directly in clinical studies of soy isoflavones.…”

Dietary phytoestrogens present in soy dramatically increase cardiotoxicity in male mice receiving a chemotherapeutic tyrosine kinase inhibitor

“…Like other endocrine disruptors, genistein induces biphasic cellular responses. In cardiomyocytes, for example, concentrations of genistein present in the plasma of individuals taking soy supplements produce both cardioprotection as well as toxicity (3–5). At lower concentrations (<1µM), genistein binds to estrogen receptors (6), producing results that are though to be largely beneficial though the cardioprotective effects of genistein and soy remain controversial (7).…”