CD146-HIF-1α hypoxic reprogramming drives vascular remodeling and pulmonary arterial hypertension

被引：128

作者：

Luo, Yongting ^{[1
]}

Teng, Xiao ^{[2
,3
]}

Zhang, Lingling ^{[4
,5
]}

Chen, Jianan ^{[6
]}

Liu, Zheng ^{[6
]}

Chen, Xuehui ^{[6
]}

Zhao, Shuai ^{[6
]}

Yang, Sai ^{[7
]}

Feng, Jing ^{[6
]}

Yan, Xiyun ^{[6
]}

机构：

[1] China Agr Univ, Beijing Adv Innovat Ctr Food Nutr & Human Hlth, Yuanmingyuan West Rd 2, Beijing 100193, Peoples R China

[2] Chinese Acad Med Sci, Fuwai Hosp, Natl Ctr Cardiovasc Dis, State Key Lab Cardiovasc Dis, 167 North Lishi Rd, Beijing 100037, Peoples R China

[3] Peking Union Med Coll, 167 North Lishi Rd, Beijing 100037, Peoples R China

[4] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Rheumatol & Clin Immunol, 1 Shuaifuyuan, Beijing 100730, Peoples R China

[5] Peking Union Med Coll, 1 Shuaifuyuan, Beijing 100730, Peoples R China

[6] Chinese Acad Sci, Inst Biophys, Key Lab Prot & Peptide Pharmaceut, 15 Datun Rd, Beijing 100101, Peoples R China

[7] Chinese Acad Sci, Inst Biophys, Lab Anim Res Ctr, 15 Datun Rd, Beijing 100101, Peoples R China

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

基金：

国家重点研发计划;

关键词：

INDUCIBLE FACTORS; THERAPEUTIC TARGET; CD146; TRANSCRIPTION; HIF-1; FACTOR-1-ALPHA; HIF-1-ALPHA; MECHANISMS; COMMUNICATION; ANGIOGENESIS;

D O I：

10.1038/s41467-019-11500-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease of cardiopulmonary units. No cure is currently available due to an incomplete understanding of vascular remodeling. Here we identify CD146-hypoxia-inducible transcription factor 1 alpha (HIF-1 alpha) cross-regulation as a key determinant in vascular remodeling and PAH pathogenesis. CD146 is markedly upregulated in pulmonary artery smooth muscle cells (PASMCs/SMCs) and in proportion to disease severity. CD146 expression and HIF-1 alpha transcriptional program reinforce each other to physiologically enable PASMCs to adopt a more synthetic phenotype. Disruption of CD146-HIF-1 alpha cross-talk by genetic ablation of Cd146 in SMCs mitigates pulmonary vascular remodeling in chronic hypoxic mice. Strikingly, targeting of this axis with anti-CD146 antibodies alleviates established pulmonary hypertension (PH) and enhances cardiac function in two rodent models. This study provides mechanistic insights into hypoxic reprogramming that permits vascular remodeling, and thus provides proof of concept for anti-remodeling therapy for PAH through direct modulation of CD146-HIF-1 alpha cross-regulation.

引用

页数：17

共 62 条

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