Loss of prolyl hydroxylase 1 and 2 in SM22α-expressing cells prevents Hypoxia-Induced pulmonary hypertension.
Loss of prolyl hydroxylase 1 and 2 in SM22α-expressing cells prevents Hypoxia-Induced pulmonary hypertension.
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SM22α 表达细胞中脯氨酰羟化酶 1 和 2 的丢失可防止缺氧引起的肺动脉高压。
DOI：
10.1152/ajplung.00428.2022
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Cornfield,DavidN
中科院分区：
文献类型：
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作者：
Barnes,ElizabethA;Ito,Reiji;Che,Xibing;Alvira,CristinaM;Cornfield,DavidN
肺动脉高压（PAH）是一种以血管收缩和血管重塑增加为特征的疾病。肺动脉平滑肌细胞（PASMCs）高表达缺氧诱导因子-1 α（HIF-1α），但其在肺动脉高压发生发展中的作用仍存在争议。为了研究SMC HIF-1α在急性和慢性缺氧肺血管反应中的作用，我们使用功能获得策略，通过在SM 22 α表达细胞中产生缺乏脯氨酰羟化酶结构域（PHD）1和2的小鼠来稳定PASMC中的HIF-1α。该策略在常氧和缺氧条件下增加HIF-1α表达和转录活性。急性缺氧增加了对照组的右心室收缩压（RVSP），但在SM 22 α-PHD 1/2−/−小鼠中没有。慢性缺氧增加RVSP和血管重塑在对照SM 22 α-PHD 1/2+/+比SM 22 α-PHD 1/2−/−小鼠更多。体外研究表明，在常氧和缺氧条件下，与PHD 1/2−/−PASMC相比，分离的PHD 1/2+/+的收缩性和肌球蛋白轻链磷酸化增加。慢性缺氧后，与SM 22 α-PHD 1/2+/+小鼠相比，SM 22 α-PHD 1/2−/−小鼠中p27表达更多，血管重塑较少。缺氧增加p27在从对照患者分离的PASMC中，但在特发性肺动脉高压（IPAH）患者的细胞中不增加。这些发现强调了HIF-1α在抑制肺血管收缩和血管重塑中的SM 22 α表达细胞特异性作用。调节PASMC中HIF-1α的表达可能代表了PAH患者有希望的预防和治疗策略。新&值得注意的是在一个小鼠模型中，低氧诱导因子1 α（HIF-1α）在血管平滑肌细胞中稳定，我们发现HIF-1α通过限制肌球蛋白轻链的磷酸化来调节血管收缩，并通过p27诱导来调节血管重塑。这些发现强调了HIF-1α在抑制肺血管收缩和血管重塑中的细胞特异性作用。
Pulmonary arterial hypertension (PAH) is a disease characterized by increased vasoconstriction and vascular remodeling. Pulmonary artery smooth muscle cells (PASMCs) highly express the transcription factor hypoxia-inducible factor-1α (HIF-1α), yet the role of PASMC HIF-1α in the development of PAH remains controversial. To study the role of SMC HIF-1α in the pulmonary vascular response to acute and chronic hypoxia, we used a gain-of-function strategy to stabilize HIF-1α in PASMC by generating mice lacking prolyl hydroxylase domain (PHD) 1 and 2 in SM22α-expressing cells. This strategy increased HIF-1α expression and transcriptional activity under conditions of normoxia and hypoxia. Acute hypoxia increased right ventricular systolic pressure (RVSP) in control, but not in SM22α-PHD1/2−/−mice. Chronic hypoxia increased RVSP and vascular remodeling more in control SM22α-PHD1/2+/+than in SM22α-PHD1/2−/−mice. In vitro studies demonstrated increased contractility and myosin light chain phosphorylation in isolated PHD1/2+/+compared with PHD1/2−/−PASMC under both normoxic and hypoxic conditions. After chronic hypoxia, there was more p27 and less vascular remodeling in SM22α-PHD1/2−/−compared with SM22α-PHD1/2+/+mice. Hypoxia increased p27 in PASMC isolated from control patients, but not in cells from patients with idiopathic pulmonary arterial hypertension (IPAH). These findings highlight an SM22α-expressing cell-specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling. Modulating HIF-1α expression in PASMC may represent a promising preventative and therapeutic strategy for patients with PAH.NEW & NOTEWORTHYIn a mouse model wherein hypoxia-inducible factor 1 alpha (HIF-1α) is stabilized in vascular smooth muscle cells, we found that HIF-1α regulates vasoconstriction by limiting phosphorylation of myosin light chain and regulates vascular remodeling through p27 induction. These findings highlight a cell-specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling.