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

Abstract

HIV protease inhibitor (PI) ritonavir (RTV) may cause vascular injury through oxidative stress. Our purpose in this study was to determine whether equol, a soy isoflavone, could prevent RTV-induced endothelial dysfunction in porcine pulmonary arteries and in human pulmonary artery endothelial cells (HPAEC). Fresh porcine pulmonary artery rings were treated with 15 micromol/L of RTV and/or equol in concentrations of 0.1, 1, and 10 micromol/L for 24 h. A control was set with no amount of equol or RTV administered. Based on myograph tension analysis, RTV significantly reduced endothelium-dependent relaxation in response to bradykinin in the artery rings compared with untreated vessels, whereas the antioxidant equol effectively reversed the RTV effect in a concentration-dependent manner. RTV also reduced the contraction of artery rings in response to thromboxane A(2) analogue U46619 and this reduction was blocked by equol. In addition, RTV treatment significantly reduced endothelial nitric oxide synthase (eNOS) expression in both porcine pulmonary arteries and HPAEC, whereas equol effectively blocked RTV-induced eNOS downregulation. Furthermore, RTV significantly increased superoxide anion production, whereas equol reversed this effect of RTV in porcine pulmonary arteries. Thus, the antioxidant equol effectively protects vascular function from the detrimental effects of HIV PI RTV in both porcine pulmonary arteries and HPAEC via a reduction in the vasomotor dysfunction, eNOS downregulation, and oxidative stress induced by RTV. These novel data suggest that equol may have a clinical application in preventing HIV-associated cardiovascular complications.

Ritonavir binds to and downregulates estrogen receptors: Molecular mechanism of promoting early atherosclerosis

“…Ouellet et al [5] reported that RTV reduces estrogen levels in the blood by 40% in healthy female volunteers. In addition, Cheng et al [3] showed that the soybean isoflavonoid equol blocks RTV-induced endothelial dysfunction in porcine pulmonary arteries and human pulmonary artery endothelial cells. These studies suggested that RTV may lead Fig.…”

“…However, more and more evidences have shown that RTV induces body fat changes and metabolic abnormalities, and many patients have developed premature atherosclerosis [1][2][3]. These side effects induced by PI have prevented the broad application of PIs.…”

“…For example, estrogens and isoflavonoid phytoestrogens protect cardiovascular tissues from developing atherosclerotic lesions [2][3][4]. In addition, RTV reduce ethinyl estradiol level in blood by 40%, which is the major estrogen component in oral contraceptives [5].…”

Pulmonary Hypertension Is a Probable NO/ONOO−Cycle Disease: A Review

“…PAH has been shown to be caused by the anti-HIV protease drug ritonavir [117][118][119]. It apparently does this, at least in part, via increased oxidative stress, because multiple chainbreaking antioxidants greatly lower this effect of the drug [117][118][119]. Ritonavir has been shown to increase superoxide production [117,120] in mitochondria [121], showing that both superoxide and mitochondrial dysfunction have roles here.…”

“…PAH has been shown to be caused by the anti-HIV protease drug ritonavir [117][118][119]. It apparently does this, at least in part, via increased oxidative stress, because multiple chainbreaking antioxidants greatly lower this effect of the drug [117][118][119].…”