phenanthrenes and Calcinosis

In calcific aortic valve disease (CAVD), the valve interstitial cells (VIC) osteogenic phenotype changes can lead to thickening and calcification of the valve leaflets，eventually lead to restricted valve movement and life-threatening. This study aims to investigate the effect and mechanism of dihydrotanshinone I (DHI) on osteogenic medium (OM) induced osteogenic phenotypic transition of porcine valve interstitial cells (PVICs), which can provide theoretical and scientific basis for clinical intervention in CAVD.. Immunohistochemical methods were used to detect the expression of osteogenic indicators Runx2, OPN and inflammation indicators IL-1β and p-NF-κB in valve specimens of CAVD patients(N = 3) and normal controls(N = 1). PVICs stimulated by osteoblastic medium (OM) were treated with or without DHI. CCK8, ALP and Alizarin Red S staining were used to detect cell growth and calcification, respectively. The results showed that under the treated with DHI, compared with OM, the formation of calcium nodules was reduced, and the expression of calcification-related markers Runx2 and OPN were down-regulated, which quantified by qRT-PCR and western blot. In addition, on the basis of OM induction, DHI also inhibited the phosphorylation of the NF-κB/ERK1/2 and SMAD1/5/8 signaling pathway.. DHI (10 μM) treatment can reverse the osteogenic phenotypic transition of PVICs induced by osteogenic medium, and the mechanism may be related to NF-κB、ERK 1/2 and Smad1/5/8 pathways.

Topics: Animals; Aortic Valve; Aortic Valve Stenosis; Calcinosis; Cell Differentiation; Cells, Cultured; Down-Regulation; Furans; Humans; MAP Kinase Signaling System; NF-kappa B; Osteoblasts; Osteogenesis; Phenanthrenes; Quinones; Signal Transduction; Smad Proteins; Swine

We have previously proved that oxidized low-density lipoprotein (oxLDL), a proatherogenic lipoprotein, plays a pivotal role in the development of atherosclerotic calcification (AC). The present study was performed to investigate whether tanshinone II A (TS II A), an anti-oxidant which has been shown to inhibit in vitro oxidation of LDL, has the effects to inhibit AC in rat model and by which, if any, mechanisms.. Rat AC model was induced by excessive vitamin D(2) (VD) and high cholesterol diet (HCD), which was proven to be successful histopathologically and biochemically.. Administration of AC rats with TS II A (35, 70 mg/kg) dose-dependently attenuated the AC pathological changes, meanwhile reduced the vessel contents of lipid and calcium. However, TS II A had no effects on serum levels of lipids, calcium and 25-OH VD. Further studies revealed that TS II A decreased serum concentration of oxLDL, reduced the superoxide anion production and malondialdehyde (MDA) in vessel. In addition, TS II A increased vessel Cu/Zn SOD activity, upregulated vessel mRNA and protein expression of Cu/Zn SOD.. The results suggested that TS II A significantly attenuated the AC in rat model, which might be attributed to its inhibition of oxLDL production independent of the serum levels of lipids, calcium and 25-OH VD, and that increasing of Cu/Zn SOD activity as well as mRNA and protein expression by TS II A might protect LDL against oxidation induced by superoxide anion in vessel.

Topics: Abietanes; Animals; Antioxidants; Aorta, Thoracic; Atherosclerosis; Calcinosis; Calcium; Cholesterol; Cholesterol, Dietary; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Induction; Ergocalciferols; Lipoproteins, LDL; Male; Malondialdehyde; Oxidative Stress; Phenanthrenes; Rats; Rats, Sprague-Dawley; RNA, Messenger; Superoxide Dismutase; Superoxides; Time Factors