phenanthrenes and Aortic-Valve-Stenosis

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

Minocycline, a tetracycline derivate, mediates vasculoprotective effects independent of its antimicrobial properties. Thus, minocycline protects against diabetic nephropathy and reduces neointima formation following vascular injury through inhibition of apoptosis or migration, respectively. Whether minocycline has an effect on primary atherogenesis remains unknown.. Using morphological and immunohistochemical analyses we determined de novo atherogenesis in ApoE-/- mice receiving a high fat diet (HFD) with or without minocycline treatment. The effect of minocycline on proliferation, expression of p27(Kip1) or PARP-1 (Poly [ADP-ribose] polymerase 1), or on PAR (poly ADP-ribosylation) modification in vascular smooth muscle cells (VSMC) was analyzed in ex vivo and in vitro (primary human and mouse VSMC).. Minocycline reduced plaque size and stenosis in ApoE-/- HFD mice. This was associated with a lower number and less proliferation of VSMC, reduced PAR (poly ADP-ribosylation) modification and increased p27(Kip1) expression within the plaques. In agreement with the ex vivo data minocycline reduced proliferation, PARP-1 expression, PAR modification while inducing p27 expression in human and mouse VSMC in vitro. These effects were observed at a low minocycline concentration (10 μM), which had no effect on VSMC migration or apoptosis. Minocycline inhibited PARP-1 and induced p27(Kip1) expression in VSMC as efficiently as the specific PARP-1 inhibitor PJ 34. Knock down of p27(Kip1) abolished the antiproliferative effect of minocycline. These data establish a novel antiatherosclerotic mechanism of minocycline during de novo atherogenesis, which depends on p27(Kip1) mediated inhibition of VSMC proliferation.

Topics: Animals; Aortic Valve Stenosis; Apolipoproteins E; Atherosclerosis; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p27; Diet, High-Fat; Humans; Mice; Minocycline; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenanthrenes; Plaque, Atherosclerotic; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases