Reoxygenation Reverses Hypoxic Pulmonary Arterial Remodeling by Inducing Smooth Muscle Cell Apoptosis via Reactive Oxygen Species-Mediated Mitochondrial Dysfunction.

Pulmonary arterial remodeling, a main characteristic of hypoxic pulmonary hypertension, can gradually reverse once oxygen has been restored. Previous studies documented that apoptosis increased markedly during the reversal of remodeled pulmonary arteries, but the types of cells and mechanisms related to the apoptosis have remained elusive. This study aimed to determine whether pulmonary artery smooth muscle cell (PASMC)-specific apoptosis was involved in the reoxygenation-induced reversal of hypoxic pulmonary arterial remodeling and elucidate the underlying mechanism. Hypoxic pulmonary hypertension was induced in adult male Sprague-Dawley rats (n=6/group) by chronic hypobaric hypoxia. and the hypoxic pulmonary hypertension rats were then transferred to a normoxia condition. During reoxygenation, hypoxia-induced pulmonary arterial remodeling gradually reversed. The reversal of remodeled pulmonary arteries was associated with increased H2O2 and with changes in lung expression of cleaved caspase3/PARP, Bax, and Bcl-2, consistent with increased apoptosis. The PASMC apoptosis, in particular, increased remarkably during this reversal. In vitro, reoxygenation induced the apoptosis of cultured rat primary PASMCs accompanied by increased mitochondrial reactive oxygen species, mitochondrial dysfunction, and the release of cytochrome C from mitochondria to cytoplasm. Clearance of reactive oxygen species alleviated mitochondrial dysfunction as well as the release of cytochrome C and, finally, decreased PASMC apoptosis. Reoxygenation-induced apoptosis of PASMCs is implicated in the reversal of hypoxic pulmonary arterial remodeling, which may be attributed to the mitochondrial reactive oxygen species-mediated mitochondrial dysfunction.

Chen J ，Wang YX ，Dong MQ ，Zhang B ，Luo Y ，Niu W ，Li ZC ... -  《Journal of the American Heart Association》

Hypoxia induces pulmonary artery smooth muscle dysfunction through mitochondrial fragmentation-mediated endoplasmic reticulum stress.

Zhuan B ，Wang X ，Wang MD ，Li ZC ，Yuan Q ，Xie J ，Yang Z ... -  《Aging-US》

Vascular peroxidase 1 mediates hypoxia-induced pulmonary artery smooth muscle cell proliferation, apoptosis resistance and migration.

Reactive oxygen species (ROS) play essential roles in the pulmonary vascular remodelling associated with hypoxia-induced pulmonary hypertension (PH). Vascular peroxidase 1 (VPO1) is a newly identified haeme-containing peroxidase that accelerates oxidative stress development in the vasculature. This study aimed to determine the potential role of VPO1 in hypoxia-induced PH-related vascular remodelling. The vascular morphology and VPO1 expression were assessed in the pulmonary arteries of Sprague-Dawley (SD) rats. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) and VPO1 expression and HOCl production were significantly increased in hypoxic rats, which also exhibited obvious vascular remodelling. Furthermore, a hypoxia-induced PH model was generated by exposing primary rat pulmonary artery smooth muscle cells (PASMCs) to hypoxic conditions (3% O2, 48 h), which significantly increased the expression of NOX4 and VPO1 and the production of HOCl. These hypoxic changes were accompanied by enhanced proliferation, apoptosis resistance, and migration. In PASMCs, hypoxia-induced changes, including effects on the expression of cell cycle regulators (cyclin B1 and cyclin D1), apoptosis-related proteins (bax, bcl-2, and cleaved caspase-3), migration promoters (matrix metalloproteinases 2 and 9), and NF-κB expression, as well as the production of HOCl, were all inhibited by silencing VPO1 with small interfering RNAs. Moreover, treatment with HOCl under hypoxic conditions upregulated NF-κB expression and enhanced proliferation, apoptosis resistance, and migration in PASMCs, whereas BAY 11-7082 (an inhibitor of NF-κB) significantly inhibited these effects. Collectively, these results demonstrate that VPO1 promotes hypoxia-induced proliferation, apoptosis resistance, and migration in PASMCs via the NOX4/VPO1/HOCl/NF-κB signalling pathway.

You B ，Liu Y ，Chen J ，Huang X ，Peng H ，Liu Z ，Tang Y ，Zhang K ，Xu Q ，Li X ，Cheng G ，Shi R ，Zhang G ... -  《-》

Selenoprotein P Promotes the Development of Pulmonary Arterial Hypertension: Possible Novel Therapeutic Target.

Kikuchi N ，Satoh K ，Kurosawa R ，Yaoita N ，Elias-Al-Mamun M ，Siddique MAH ，Omura J ，Satoh T ，Nogi M ，Sunamura S ，Miyata S ，Saito Y ，Hoshikawa Y ，Okada Y ，Shimokawa H ... -  《-》

Involvement of Gax gene in hypoxia-induced pulmonary hypertension, proliferation, and apoptosis of arterial smooth muscle cells.

Xia S ，Tai X ，Wang Y ，An X ，Qian G ，Dong J ，Wang X ，Sha B ，Wang D ，Murthi P ，Kalionis B ，Wang X ，Bai C ... -  《-》