| First Author | Liu Z | Year | 2023 |
| Journal | Metabolism | Volume | 138 |
| Pages | 155337 | PubMed ID | 36273649 |
| Mgi Jnum | J:348719 | Mgi Id | MGI:7387970 |
| Doi | 10.1016/j.metabol.2022.155337 | Citation | Liu Z, et al. (2022) Long noncoding TSI attenuates aortic valve calcification by suppressing TGF-beta1-induced osteoblastic differentiation of valve interstitial cells. Metabolism :155337 |
| abstractText | INTRODUCTION: Calcific aortic valve disease (CAVD) is an active and cellular-driven fibrocalcific process characterised by differentiation of valve interstitial cells (VICs) towards an osteogenic-like phenotype. A recently identified lncRNA, lncTSI, has been reported to inhibit fibrogenesis through transforming growth factor (TGF)-beta/Smad3 pathway. Here, the present study aimed to investigate the role of lncTSI in CAVD. METHODS: The effect of TGF-beta1 on lncTSI of VICs was measured. TGF-beta1, RUNX2 and collagen I expression between calcified aortic valve tissue and normal samples by immunohistochemistry and western blotting. Human VICs were cultured and treated with TGF-beta1. SiRNA and pcDNA3.1-lncTSI plasmid transfection were used to silence and overexpress lncTSI in VICs for 48 h, Smads phosphorylation, RUNX2 and collagen I expression were then verified by western blotting. In ApoE(-/-) mice fed with 0.25 % high-cholesterol diet, AAV2-lncTSI were injected intravenously to observe their effect on the formation of aortic valve calcification. RESULTS: lncTSI was highly expressed in VICs treated with TGF-beta1. lncTSI was transcriptionally regulated by Smad3 and reversely inhibited TGF-beta1-induced Smad3 phosphorylation and downregulated profibrotic gene expression. Silencing lncTSI increased TGF-beta1-induced Smad3 phosphorylation, and subsequently, upregulated RUNX2 and collagen I expressions in VICs. While overexpression of lncTSI reversed the production of RUNX2 and collagen I in VICs. In a mouse CAVD model of 24 week 0.25 % high-cholesterol diet feeding, overexpression of lncTSI significantly reduced calcium deposition, RUNX2, pSmad3, and collagen I expression in aortic valve leaflets, with less aortic valve stenosis. CONCLUSIONS: The novel findings of present study suggested that lncTSI alleviated aortic valve calcification through negative regulation of the TGF-beta/Smad3 pathway. The results may help elucidate new diagnostic and therapeutic targets to prevent CAVD progression. |
