ERK/Drp1-dependent mitochondrial fission contributes to HMGB1-induced autophagy in pulmonary arterial hypertension.
ERK/Drp1-dependent mitochondrial fission contributes to HMGB1-induced autophagy in pulmonary arterial hypertension.
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DOI：
10.1111/cpr.13048
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发表时间：
2021-06
影响因子：
8.5
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
Feng W;Wang J;Yan X;Zhang Q;Chai L;Wang Q;Shi W;Chen Y;Liu J;Qu Z;Li S;Xie X;Li M
研究发现，肺动脉高压（PAH）患者的高迁移率族蛋白盒-1（HMGB 1）和由GTPase发动蛋白相关蛋白1（Drp 1）过度激活介导的异常线粒体分裂水平升高，并与肺动脉高压发病机制密切相关。然而，目前尚不清楚Drp 1是否介导线粒体分裂以及线粒体分裂的下游靶点介导HMGB 1诱导的肺动脉平滑肌细胞（PASMC）增殖和迁移，导致PAH的血管重塑。本研究旨在解决这些问题。原代培养的PASMC获自雄性Sprague-道利（SD）大鼠。我们通过qRT-PCR检测RNA水平，通过Western印迹检测蛋白水平，通过细胞计数试剂盒-8（CCK-8）和EdU掺入试验检测细胞增殖，通过伤口愈合和transwell试验检测迁移。SD大鼠腹腔注射野百合碱（MCT）建立PAH模型。通过闭胸右心导管术测量血流动力学参数。HMGB 1通过激活细胞外信号调节激酶1/2（ERK 1/2）信号通路，增加Drp 1磷酸化和依赖于Drp 1的线粒体碎片化，随后触发自噬激活，进一步导致骨形态发生蛋白受体2（BMPR 2）溶酶体降解和DNA结合抑制因子1（Id 1）下调，最终促进PASMCs增殖/迁移。抑制ERK 1/2级联反应、敲低Drp 1或抑制自噬可恢复HMGB 1诱导的BMPR 2和Id 1减少，并减少HMGB 1诱导的PASMCs增殖/迁移。此外，在MCT诱导的大鼠PAH模型中，HMGB 1的药理学抑制、Mdivi‐1的线粒体分裂抑制或氯喹的自噬阻断可预防PAH的发生。HMGB 1通过激活ERK 1/2/Drp 1/Autophagy/BMPR 2/Id 1轴促进PASMCs增殖/迁移和肺血管重构，提示该级联反应可能成为治疗PAH的潜在新靶点。PAH中HMGB 1诱导肺血管重构的分子机制。HMGB 1通过激活ERK 1/2信号通路增加Drp 1磷酸化和Drp 1依赖的线粒体分裂，随后刺激自噬激活，进而导致BMPR 2溶酶体降解和Id 1下调，最终促进PAH时PASMCs增殖/迁移和肺血管重塑。
High‐mobility group box‐1 (HMGB1) and aberrant mitochondrial fission mediated by excessive activation of GTPase dynamin‐related protein 1 (Drp1) have been found to be elevated in patients with pulmonary arterial hypertension (PAH) and critically implicated in PAH pathogenesis. However, it remains unknown whether Drp1‐mediated mitochondrial fission and which downstream targets of mitochondrial fission mediate HMGB1‐induced pulmonary arterial smooth muscle cells (PASMCs) proliferation and migration leading to vascular remodelling in PAH. This study aims to address these issues. Primary cultured PASMCs were obtained from male Sprague‐Dawley (SD) rats. We detected RNA levels by qRT‐PCR, protein levels by Western blotting, cell proliferation by Cell Counting Kit‐8 (CCK‐8) and EdU incorporation assays, migration by wound healing and transwell assays. SD rats were injected with monocrotaline (MCT) to establish PAH. Hemodynamic parameters were measured by closed‐chest right heart catheterization. HMGB1 increased Drp1 phosphorylation and Drp1‐dependent mitochondrial fragmentation through extracellular signal‐regulated kinases 1/2 (ERK1/2) signalling activation, and subsequently triggered autophagy activation, which further led to bone morphogenetic protein receptor 2 (BMPR2) lysosomal degradation and inhibitor of DNA binding 1 (Id1) downregulation, and eventually promoted PASMCs proliferation/migration. Inhibition of ERK1/2 cascade, knockdown of Drp1 or suppression of autophagy restored HMGB1‐induced reductions of BMPR2 and Id1, and diminished HMGB1‐induced PASMCs proliferation/migration. In addition, pharmacological inhibition of HMGB1 by glycyrrhizin, suppression of mitochondrial fission by Mdivi‐1 or blockage of autophagy by chloroquine prevented PAH development in MCT‐induced rats PAH model. HMGB1 promotes PASMCs proliferation/migration and pulmonary vascular remodelling by activating ERK1/2/Drp1/Autophagy/BMPR2/Id1 axis, suggesting that this cascade might be a potential novel target for management of PAH. The molecular mechanisms underlying HMGB1‐induced pulmonary vascular remodelling in PAH. HMGB1 increases Drp1 phosphorylation and Drp1‐dependent mitochondrial fission through activation of ERK1/2 signaling pathway, and subsequently stimulates autophagy activation, which further lead to BMPR2 lysosomal degradation and Id1 downregulation, and ultimately promotes PASMCs proliferation/migration and pulmonary vascular remodeling in PAH.
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DOI：
10.1161/atvbaha.119.312907
发表时间：
2019-12-01
影响因子：
8.7
作者：
Lin, Qing;Fan, Chunling;Johns, Roger A.
通讯作者：
Johns, Roger A.
DOI：
10.1165/ajrcmb.20.4.3357
发表时间：
1999-04-01
影响因子：
6.4
作者：
Jones, R;Jacobson, M;Steudel, W
通讯作者：
Steudel, W
影响因子：
6.1
作者：
El-Magd, Nada F. Abo;El-Mesery, Mohamed;El-Shishtawy, Mamdouh M.
通讯作者：
El-Shishtawy, Mamdouh M.
DOI：
10.1164/rccm.201812-2290oc
发表时间：
2019-09-01
影响因子：
24.7
作者：
Kovacs, Laszlo;Cao, Yapeng;Su, Yunchao
通讯作者：
Su, Yunchao
SIRT4 通过 ERK-Drp1 通路介导的线粒体动力学抑制 NSCLC 的恶性进展
影响因子：
8
作者：
Fu, L.;Dong, Q.;Li, Q.
通讯作者：
Li, Q.