Long noncoding TSI attenuates aortic valve calcification by suppressing TGF-β1-induced osteoblastic differentiation of valve interstitial cells

被引：13

作者：

Liu, Zongtao ^{[1
]}

Wang, Yixuan ^{[1
,3
]}

Liu, Fayuan ^{[1
]}

Zhu, Da ^{[4
]}

Chen, Yuqi ^{[1
]}

Yim, Wei Yen ^{[1
]}

Hu, Ke ^{[2
]}

Rao, Zhenqi ^{[1
]}

Pan, Xiangbin ^{[4
,5
]}

Li, Fei ^{[1
,3
,5
]}

Dong, Nianguo ^{[1
,3
,5
]}

机构：

[1] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Cardiovasc Surg, Wuhan 430022, Peoples R China

[2] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Vasc Surg, Wuhan 430022, Peoples R China

[3] Chinese Acad Med Sci, Minist Educ, NHC Key Lab Organ Transplantat, Key Lab Organ Transplantat, Wuhan, Peoples R China

[4] Kunming Med Univ, Fuwai Yunnan Cardiovasc Hosp, Struct Heart Ctr, 528 Shahebei Rd, Kunming, Peoples R China

[5] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Cardiovasc Surg, 1277 Jiefang Ave, Wuhan 430022, Peoples R China

来源：

METABOLISM-CLINICAL AND EXPERIMENTAL | 2023年 / 138卷

基金：

中国国家自然科学基金;

关键词：

Long noncoding TSI; Transforming growth factor-beta 1; Calcific aortic valve disease; Valve interstitial cells; TRANSFORMING GROWTH-FACTOR-BETA-1; DISEASE; MECHANISMS;

D O I：

10.1016/j.metabol.2022.155337

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Introduction: Calcific aortic valve disease (CAVD) is an active and cellular-driven fibrocalcific process charac-terised 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-beta 1 on lncTSI of VICs was measured. TGF-beta 1, RUNX2 and collagen I expression be-tween calcified aortic valve tissue and normal samples by immunohistochemistry and western blotting. Human VICs were cultured and treated with TGF-81. 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-beta 1. lncTSI was transcriptionally regulated by Smad3 and reversely inhibited TGF-beta 1-induced Smad3 phosphorylation and downregulated profibrotic gene expression. Silencing lncTSI increased TGF-beta 1-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.

引用

页数：15

共 31 条

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