Dihydromyricetin ameliorates vascular calcification in chronic kidney disease by targeting AKT signaling

Abstract

Vascular calcification is highly prevalent in chronic kidney disease (CKD), and characterized by trans-differentiation from contractile vascular smooth muscle cells (VSMCs) into an osteogenic phenotype. However, no effective and therapeutic option to prevent vascular calcification is yet available. Dihydromyricetin (DMY), a bioactive flavonoid isolated from Ampelopsis grossedentata, has been found to inhibit VSMCs proliferation and the injury-induced neointimal formation. However, whether DMY has an effect on osteogenic differentiation of VSMCs and vascular calcification is still unclear. In this study, we sought to investigate the effect of DMY on vascular calcification in CKD and the underlying mechanism. DMY treatment significantly attenuated calcium/phosphate-induced calcification of rat and human VSMCs in a dose-dependent manner, as shown by alizarin red S staining and calcium content assay, associated with down-regulation of osteogenic markers including type I collagen (COL I), RUNX2, BMP2 and osteocalcin (OCN). These results were further confirmed in aortic rings ex vivo. Moreover, DMY ameliorated vascular calcification in rats with CKD. Additionally, we found that AKT signaling was activated during vascular calcification, whereas significantly inhibited by DMY administration. DMY treatment significantly reversed AKT activator-induced vascular calcification. Furthermore, inhibition of AKT signaling efficiently attenuated calcification, which was similar to that after treatment with DMY alone, and DMY had a better inhibitory effect on calcification as compared to AKT inhibitor. The present study demonstrated that DMY has a potent inhibitory role in vascular calcification partially by inhibiting AKT activation, suggesting that DMY may act as a promising therapeutic candidate for patients suffering from vascular calcification.

Dihydromyricetin ameliorates osteogenic differentiation of human aortic valve interstitial cells by targeting c-KIT/interleukin-6 signaling pathway

“…Whether DHM exhibits a protective role against CAVD progression in humans requires further study. Our present study demonstrated that DHM prevents the osteogenic differentiation of hVICs via a c-KIT/IL-6dependent pathway at noncytotoxic concentrations of 20 μM, as evidenced by decreased protein levels of two osteogenesisspecific genes (ALP and Runx2) and calcified nodule formation, which is consistent with several previous findings involving the protective role of DHM in atherosclerosis and vascular calcification (Liu et al, 2017;Yang et al, 2020;Feng et al, 2021). In addition, a recent study indicated that DHM significantly suppressed foam cell formation by regulating cholesterol efflux in macrophages (Zeng et al, 2018), thereby protecting ApoE −/− mice from atherosclerosis.…”

“…Mounting evidence suggests that DHM exhibits cardiovascular protective properties in cardiovascular diseases, such as vascular calcification ( Feng et al, 2021 ), endothelial protection ( Chen et al, 2021 ), and pulmonary arterial hypertension ( Li Q et al, 2017 ). In atherosclerosis, which shares similar pathological features with CAVD ( Kostyunin et al, 2020 ), DHM has been shown to increase endothelial nitric oxide production in apolipoprotein E-deficient mice (ApoE −/− ) ( Yang et al, 2020 ) and protect human umbilical vein endothelial cells from oxidative damage ( Zhang et al, 2019 ).…”

“…Ampelopsis grossedentata (also known as vine tea) is a traditional Chinese edible herb widely consumed not only as a healthy tea but also as a medicinal herb that possesses numerous pharmacological activities. Dihydromyricetin (DHM), the most bioactive constituent of ampelopsis grossedentata, has increasingly drawn attention as an effective drug for the treatment of cardiovascular diseases, including vascular calcification ( Feng et al, 2021 ), myocardial hypertrophy ( Chen et al, 2018 ), doxorubicin-induced cardiotoxicity ( Sun et al, 2020 ), and cardiac ischemia/reperfusion injury ( Wei et al, 2019 ). Specifically, Yang et al reported that DHM could ameliorate the progression of atherosclerosis in low-density lipoprotein receptor-deficient (LDLr −/− ) mice by countering hyperlipidemia and aortic inflammation ( Liu et al, 2017 ).…”

Prevotella copri promotes vascular calcification via lipopolysaccharide through activation of NF-κB signaling pathway

“…The VC model was performed as described previously. 7 , 8 , 22 In brief, rats were anaesthetized with sodium pentobarbital (50 mg/kg) via intraperitoneal injection. Subsequently, a 2/3 right nephrectomy was performed, followed by the complete removal of the left kidney a week later to induce CKD.…”

“…Primary rat VSMCs were obtained from the thoracic aortas of 2-month-old male Sprague-Dawley rats using the explant method detailed in our prior studies. 7 , 8 , 22 In brief, the rats were euthanized intraperitoneally with sodium pentobarbital (150 mg/kg) for aortic isolation. The aortas were dissected, longitudinally opened with sterile scissors, and then segmented into small pieces under sterile conditions.…”