Necrosis-Released HMGB1 (High Mobility Group Box 1) in the Progressive Pulmonary Arterial Hypertension Associated With Male Sex.
Necrosis-Released HMGB1 (High Mobility Group Box 1) in the Progressive Pulmonary Arterial Hypertension Associated With Male Sex.
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DOI：
10.1161/hypertensionaha.120.16118
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Rafikova O
中科院分区：
文献类型：
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作者：
Zemskova M;McClain N;Niihori M;Varghese MV;James J;Rafikov R;Rafikova O
损伤相关的分子模式，如HMGB1，在肺动脉高压(PAH)的发展中发挥着公认的作用，PAH是一种进行性致命的肺血管疾病。然而，特定类型的血管细胞、细胞死亡类型或释放的HMGB1在PAH中的作用尚不清楚。此外，尽管男性PAH患者表现出较高水平的循环HMGB1，但其与男性严重PAH表型的关系尚不清楚。在这项研究中，我们旨在研究从受损的血管细胞中释放的HMGB1的来源和活性形式，以及它们在男性进展型PAH中的作用。我们的结果表明，HMGB1是由经历坏死细胞死亡的人肺动脉内皮细胞(HPAEC)或人血管内皮细胞(HPASMC)释放的，尽管在细胞凋亡过程中只有HPASMC产生HMGB1。此外，只有HPASMC死亡才能诱导二聚体HMGB1的释放和TLR4的激活。改良的SUGEN/低氧大鼠模型复制了人类在PAH严重程度上的性别二态(男性右室收缩压为54.7±2.3，女性为44.6±2毫米汞柱)。通过这个模型，我们证实了坏死性下垂和坏死是雄性大鼠循环HMGB1的主要来源，尽管只有坏死性增加了HMGB1二聚体的循环。坏死的减少，而不是细胞凋亡或坏死性下垂的减少，阻止了男性TLR4的激活，并削弱了PAH严重程度的性别差异。我们得出结论，通过HMGB1二聚体的释放，坏死使男性易患进行性PAH。HMGB1的释放和活性取决于血管细胞的类型、细胞死亡的类型和释放的HMGB1的形式。在PAH的临床前模型中，从坏死细胞中释放的HMGB1促进了雄性啮齿动物的PAH严重程度，提示它参与了进行性PAH和男性PAH患者不良的生存预后。
Damage-associated molecular patterns, such as HMGB1, play a well-recognized role in the development of pulmonary arterial hypertension (PAH), a progressive fatal disease of the pulmonary vasculature. However, the contribution of the particular type of vascular cells, type of cell death, or the form of released HMGB1 in PAH remains unclear. Moreover, although male PAH patients show a higher level of circulating HMGB1, its involvement in the severe PAH phenotype reported in males is unknown. In this study, we aimed to investigate the sources and active forms of HMGB1 released from damaged vascular cells and their contribution to the progressive type of PAH in males. Our results showed that HMGB1 is released by either pulmonary artery human endothelial (HPAEC) or human smooth muscle cells (HPASMC) that underwent necrotic cell death, although only HPASMC produce HMGB1 during apoptosis. Moreover, only HPASMC death induced a release of dimeric HMGB1, found to be mitochondrial reactive oxygen species dependent, and TLR4 activation. The modified Sugen/Hypoxia rat model replicates the human sexual dimorphism in PAH severity (right ventricle systolic pressure in males vs. females 54.7±2.3 vs. 44.6±2 mmHg). By using this model, we confirmed that necroptosis and necrosis are the primary sources of circulating HMGB1 in the male rats, although only necrosis increased circulation of HMGB1 dimers. Attenuation of necrosis but not apoptosis or necroptosis prevented TLR4 activation in males and blunted the sex differences in PAH severity. We conclude that necrosis, through the release of HMGB1 dimers, predisposes males to a progressive form of PAH. HMGB1 release and activity depend on the type of vascular cells, type of cell death, and form of released HMGB1. HMGB1 released from necrotic cells promotes PAH severity in male rodents in the preclinical model of PAH, suggesting its involvement in progressive PAH and poor survival prognosis in male patients with PAH.