Cardiovascular Protective Effects of Synthetic Isoflavone Derivatives in Apolipoprotein E-Deficient Mice

Abstract

Dietary flavonoids are thought to protect against cardiovascular disease. We have studied the effects of bioactive isoflavone metabolites on hyperlipidemia, endothelial dysfunction and the development of atherosclerotic lesions in apolipoprotein E-deficient (apoE⁰) mice fed a Western high-fat diet. Supplementation with dihydrodaidzein (DiD), dehydroequol (DeE) (both 25 mg kg^–1· day^–1) and their combination (D/D; 12.5 mg kg^–1·day^–1 for each) for 24 weeks reduced plasma high-density lipoprotein (HDL) and non-HDL cholesterol. D/D also reduced the triglyceride level. In the abdominal aorta of apoE⁰ mice, these compounds significantly increased endothelial nitric oxide (NO)-mediated vasorelaxations induced by acetylcholine, but had a minor effect on relaxations induced by the NO donor S-nitroso-N-acetylpenicillamine. Isoflavone treatment for 24 weeks had no effect on the total area of atherosclerotic plaques in the whole aorta, but DeE reduced the plaque thickness in the aortic arch by 29%, although this did not reach statistical significance. The endothelial dysfunction in apoE⁰ mice is associated with hyperlipidemia and increased vascular oxidative stress measured as increased superoxide production. Both isoflavones have superoxide-scavenging activities in vitro. We suggest that chronic supplementation with bioactive isoflavone metabolites may protect endothelial NO function in apoE⁰ mice, through both lipid-lowering and antioxidant actions.