CD146-HIF-1α hypoxic reprogramming drives vascular remodeling and pulmonary arterial hypertension
CD146-HIF-1α hypoxic reprogramming drives vascular remodeling and pulmonary arterial hypertension
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DOI：
10.1038/s41467-019-11500-6
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发表时间：
2019-08-07
影响因子：
16.6
通讯作者：
Yan, Xiyun
中科院分区：
文献类型：
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作者：
Luo, Yongting;Teng, Xiao;Yan, Xiyun
肺动脉高压（PAH）是一种心肺单位的血管重构性疾病。由于对血管重塑的了解不完全，目前没有治愈方法。在这里，我们确定了CD 146-缺氧诱导转录因子1 α（HIF-1 α）的交叉调节作为血管重塑和PAH发病机制的关键决定因素。CD 146在肺动脉平滑肌细胞（PASMC/SMC）中显著上调，并与疾病严重程度成比例。CD 146表达和HIF-1 α转录程序相互加强，使PASMC在生理上能够采用更合成的表型。通过基因消融SMC中的Cd 146来破坏CD 146-HIF-1 α的串扰减轻慢性缺氧小鼠的肺血管重构引人注目的是，在两种啮齿动物模型中，用抗CD 146抗体靶向该轴可消除已建立的肺动脉高压（PH）并增强心脏功能。这项研究提供了对缺氧重编程的机制见解，允许血管重塑，从而通过直接调节CD 146-HIF-1 α交叉调节为PAH的抗重塑治疗提供了概念证据。
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.