Apigenin restores endothelial function by ameliorating oxidative stress, reverses aortic stiffening, and mitigates vascular inflammation with aging

Abstract

We assessed the efficacy of oral supplementation with the flavanoid apigenin on arterial function during aging and identified critical mechanisms of action. Young (6 months) and old (27 months) C57BL/6N mice (model of arterial aging) consumed drinking water containing vehicle (0.2% carboxymethylcellulose; 10 young, 7 old) or apigenin (0.5 mg/ml in vehicle; 10 young, 9 old) for 6 weeks. In vehicle-treated animals, isolated carotid artery endothelium-dependent dilation (EDD), bioassay of endothelial function, was impaired in old vs young (70±9 vs 92±1 %, P<0.0001) due to reduced nitric oxide (NO) bioavailability. Old mice had greater arterial reactive oxygen species (ROS) production and oxidative stress (higher nitrotyrosine) associated with greater nicotinamide adenine dinucleotide phosphate oxidase (oxidant enzyme) and lower superoxide dismutase 1 and 2 (antioxidant enzymes); ex vivo administration of TEMPOL (antioxidant) restored EDD to young levels, indicating ROS-mediated suppression of EDD. Old animals also had greater aortic stiffness as indicated by higher aortic pulse wave velocity (PWV, 434±9 vs 346±5 cm/sec, P<0.0001) due to greater intrinsic aortic wall stiffness associated with lower elastin levels and higher collagen, advanced glycation end-products (AGEs) and pro-inflammatory cytokine abundance. In old mice, apigenin restored EDD (96±2%) by increasing NO bioavailability, normalized arterial ROS, oxidative stress and antioxidant expression, and abolished ROS inhibition of EDD. Moreover, apigenin prevented foam cell formation in vitro (initiating step in atherosclerosis) and mitigated age-associated aortic stiffening (PWV 373±5 cm/sec) by normalizing aortic intrinsic wall stiffness, collagen, elastin, AGEs, and inflammation. Thus, apigenin is a promising therapeutic for arterial aging.

Current Status and Future Perspectives on Therapeutic Potential of Apigenin: Focus on Metabolic-Syndrome-Dependent Organ Dysfunction

“…Apigenin has also been shown to precondition the heart against susceptibility to infarction; in particular, this flavone reversed vascular endothelial dysfunction in a cell culture model of early atherosclerosis, suppressing arterial ROS production and oxidative stress and protecting the heart against I/R damage [96]. In this regard, nutritional preconditioning with apigenin improved cardiac function in rats exposed to I/R by decreasing lipid peroxidation and enhancing SOD, glutathione peroxidase (GPX) and catalase (CAT) myocardial activities in a mechanism that targets a mitochondrial pathway mediated by the Notch1/Hes1 signalling [97].…”

Pharmacokinetic, Metabolism, and Metabolomic Strategies Provide Deep Insight Into the Underlying Mechanism of Ginkgo biloba Flavonoids in the Treatment of Cardiovascular Disease

“…The flavones in G. biloba mainly include apigenin, luteolin, and chrysanthin, the cardioprotective mechanism of which were summarized in Supplementary Table 1 . Apigenin can protect vascular endothelial ( 17 , 18 ), reduce myocardial damage ( 19 , 20 ), serve as anticoagulant ( 21 ), and prevent aortic aneurysm ( 22 ). Not only could apigenin improve the functional recovery of ischemic heart through PI3K/Akt pathway and reduce myocardial infarction size, but it also could downregulate the activities of creatine kinase isoenzyme and lactate dehydrogenase in coronary blood flow, and minimize the number of apoptotic cardiomyocytes.…”

NAD+ and Vascular Dysfunction: From Mechanisms to Therapeutic Opportunities

“… 45 In old mice, apigenin rescued endothelial dysfunction, which was associated with increased NO bioavailability, normalized arterial ROS, and reduced oxidative stress. 46 Additionally, in vitro , apigenin prevented the formation and accumulation of foam cells, which are known to propagate the development of atherosclerotic lesions, and alleviated age-associated aortic stiffening, reducing adverse remodeling of the extracellular matrix and suppressing vascular inflammation. Considering that apigenin is a Food and Drug Administration-approved dietary supplement, these preclinical findings provide an experimental basis for future translational studies testing the potential of this CD38 inhibitor to improve arterial dysfunction and reduce vascular disease risk in the elderly.…”