Nanoparticle endothelial delivery of PGC-1α attenuates hypoxia-induced pulmonary hypertension by attenuating EndoMT-caused vascular wall remodeling.
Nanoparticle endothelial delivery of PGC-1α attenuates hypoxia-induced pulmonary hypertension by attenuating EndoMT-caused vascular wall remodeling.
复制标题
DOI：
10.1016/j.redox.2022.102524
复制
发表时间：
2022-12
期刊：
影响因子：
11.4
通讯作者：
Chen, Shi-You
中科院分区：
文献类型：
--
作者：
Cai, Dunpeng;Chen, Shi-You
关键词：
慢性缺氧引起的肺动脉高压（PH）以肺动脉壁增厚、肺血管阻力升高和右心衰竭为特征。内皮细胞功能障碍是PH进展的标志性事件。在各种机制中，内皮细胞向间质转化（EndoMT）已成为PH中内皮细胞功能障碍的重要来源。然而，PH中EndoMT的潜在机制在很大程度上仍然未知。结果显示，与正常对照组相比，PH患者和低氧诱导的PH小鼠模型肺动脉内皮细胞（PAECs）中过氧化物酶体增殖物激活受体γ共激活因子1 α（PGC-1α）表达降低。使用纳米颗粒递送的PGC-1α的内皮特异性过表达显著减弱了PH的进展，如右心室收缩压显著降低和动脉厚度减少以及血管肌肉化减少所示。此外，在PH期间，内皮特异性PGC-1α过表达阻断PAEC的EndoMT，表明PGC-1α的缺失通过介导EndoMT促进PH的发展，这损害了内皮的完整性。有趣的是，我们发现PGC-1α过表达挽救了体内缺氧处理的小鼠肺组织和体外TGF-β处理的内皮细胞中内皮型一氧化氮合酶的表达。与此同时，PAEC和血管平滑肌共培养表明，PAEC中PGC-1α的过表达增加了一氧化氮的释放，这可能会扩散到平滑肌细胞，在那里它激活了特定的蛋白激酶，并通过减少钙流量来启动SMC松弛。PGC-1α的内皮特异性过表达也减弱了缺氧诱导的肺动脉僵硬，这似乎是由内皮一氧化氮产生减少和血管重塑增加引起的。总之，这些结果表明，PGC-1α的内皮特异性递送通过抑制PAEC的EndoMT从而恢复内皮功能并减少血管重塑来预防PH的发展。PGC-1α在肺动脉高压患者和小鼠肺动脉高压模型肺动脉内皮细胞中表达下调。PGC-1α的内皮递送减轻小鼠中缺氧诱导的PH。PGC-1α的内皮特异性表达通过抑制PAEC的EndoMT阻断PH。EC递送PGC-1α通过增加NO产生和减少血管重构来减轻肺动脉僵硬。
Pulmonary hypertension (PH) induced by chronic hypoxia is characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, and right-heart failure. Dysfunction of endothelial cells is the hallmark event in the progression of PH. Among various mechanisms, endothelial to mesenchymal transition (EndoMT) has emerged as an important source of endothelial cell dysfunction in PH. However, the mechanisms underlying the EndoMT in PH remain largely unknown. Our results showed that peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression was decreased in pulmonary arterial endothelial cells (PAECs) in PH patients and hypoxia-induced PH mouse model compared to the normal controls. Endothelial-specific overexpression of PGC-1α using nanoparticle delivery significantly attenuated the progression of PH, as shown by the significantly decreased right ventricular systolic pressure and diminished artery thickness as well as reduced vascular muscularization. Moreover, Endothelial-specific overexpression of PGC-1α blocked the EndoMT of PAECs during PH, indicating that loss of PGC-1α promotes PH development by mediating EndoMT, which damages the integrity of endothelium. Intriguingly, we found that PGC-1α overexpression rescued the expression of endothelial nitric oxide synthase in mouse lung tissues that was deceased by hypoxia treatment in vivo and in endothelial cells treated with TGF-β in vitro. Consistently, PAECs and vascular smooth muscle co-culture showed that overexpression of PGC-1α in PAECs increases nitric oxide release, which would likely diffuse to smooth muscle cells, where it activates specific protein kinases, and initiates SMC relaxation by diminishing the calcium flux. Endothelial-specific overexpression of PGC-1α also attenuated hypoxia-induced pulmonary artery stiffness which appeared to be caused by both the decreased endothelial nitric oxide production and increased vascular remodeling. Taken together, these results demonstrated that endothelial-specific delivery of PGC-1α prevents PH development by inhibiting EndoMT of PAECs and thus restoring endothelial function and reducing vascular remodeling. PGC-1α is downregulated in pulmonary artery endothelial cells of human PAH patients and mouse PH model. Endothelial delivery of PGC-1α attenuates hypoxia-induced PH in mice. Endothelial-specific expression of PGC-1α blocks PH by inhibiting EndoMT of PAECs. EC delivery of PGC-1α attenuated pulmonary artery stiffness by increasing NO production and decreasing vascular remodeling.
登录
查看更多内容
影响因子：
29
作者：
Sawada N;Jiang A;Takizawa F;Safdar A;Manika A;Tesmenitsky Y;Kang KT;Bischoff J;Kalwa H;Sartoretto JL;Kamei Y;Benjamin LE;Watada H;Ogawa Y;Higashikuni Y;Kessinger CW;Jaffer FA;Michel T;Sata M;Croce K;Tanaka R;Arany Z
通讯作者：
Arany Z
影响因子：
5.6
作者：
Rol N;Kurakula KB;Happé C;Bogaard HJ;Goumans MJ
通讯作者：
Goumans MJ
影响因子：
3.7
作者：
Nahar K;Rashid J;Absar S;Al-Saikhan FI;Ahsan F
通讯作者：
Ahsan F
影响因子：
3.8
作者：
Kawashima Y;Kodera Y;Singh A;Matsumoto M;Matsumoto H
通讯作者：
Matsumoto H
DOI：
10.1164/rccm.201304-0686pp
发表时间：
2013-09-15
影响因子：
24.7
作者：
Klinger, James R.;Abman, Steven H.;Gladwin, Mark T.
通讯作者：
Gladwin, Mark T.