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Targeting HSP90 attenuates angiotensin II-induced adventitial remodeling via suppression of mitochondrial fission.
Cardiovascular Research ( IF 10.8 ) Pub Date : 2019-07-25 , DOI: 10.1093/cvr/cvz194 Gaojian Huang 1, 2 , Zhilei Cong 3 , Xiaoyan Wang 4 , Yanggang Yuan 5 , Renjie Xu 1 , Zhaoyang Lu 1, 6 , Xuelian Wang 1, 6 , Jia Qi 1, 4
Cardiovascular Research ( IF 10.8 ) Pub Date : 2019-07-25 , DOI: 10.1093/cvr/cvz194 Gaojian Huang 1, 2 , Zhilei Cong 3 , Xiaoyan Wang 4 , Yanggang Yuan 5 , Renjie Xu 1 , Zhaoyang Lu 1, 6 , Xuelian Wang 1, 6 , Jia Qi 1, 4
Affiliation
AIMS
Adventitial remodeling presenting with the phenotypic switch of adventitial fibroblasts (AFs) to myofibroblasts (MFs) is reportedly involved in the evolution of several vascular diseases, including hypertension. In our previous study, we reported that heat shock protein 90 (HSP90) inhibition by 17-dime-thylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) markedly attenuates angiotensin II (AngII)-induced abdominal aortic aneurysm formation by simultaneously inhibiting several key signaling and transcriptional pathways in vascular smooth muscle cells (VSMCs); however, little is known about its role on AFs. Given that the AF phenotypic switch is likely to be associated with mitochondrial function and calcineurin, a client protein of HSP90 that mediates mitochondrial fission and function, the aim of this study was to investigate whether mitochondrial fission contributes to phenotypic switch of AF, and if it does, we further aimed to determine whether HSP90 inhibition attenuates mitochondrial fission and subsequently suppresses AF transformation and adventitial remodeling in AngII-induced hypertensive mice.
METHODS AND RESULTS
In primary mouse AFs, we found that calcineurin-dependent dephosphorylation of Drp1 induced mitochondrial fission and regulated mitochondrial ROS production, which stimulated AF proliferation, migration, and phenotypic switching in AngII-treated AFs. Moreover, AngII was found to increase the binding of HSP90 and calcineurin in AFs, while HSP90 inhibition significantly reversed AngII-induced mitochondrial fission and AF phenotypic switching by modulating the calcineurin-dependent dephosphorylation of Drp1. Consistent with the effects in AFs, in an animal model of AngII-induced adventitial remodeling, 17-DMAG markedly reduced mitochondrial fission, AF differentiation, vessel wall thickening, and fibrosis in the aortic adventitia, which were mediated by calcineurin/Drp1 signaling pathways.
CONCLUSIONS
Our study suggests that calcineurin/Drp1-dependent mitochondrial fission may be essential for understanding adventitial remodeling in hypertension and that HSP90 inhibition may serve as a novel approach for the treatment of adventitial remodeling-related diseases.
中文翻译:
靶向HSP90通过抑制线粒体裂变来减弱血管紧张素II诱导的外膜重塑。
据报道,AIMS房室重塑表现为外膜成纤维细胞(AFs)向肌成纤维细胞(MFs)的表型转换,据报道与包括高血压在内的几种血管疾病有关。在我们之前的研究中,我们报道了热抑制蛋白90(HSP90)被17-二甲基-乙基氨基乙基氨基-17-去甲氧基格尔德霉素(17-DMAG)抑制,通过同时抑制几种关键信号传导显着减弱了血管紧张素II(AngII)诱导的腹主动脉瘤的形成。血管平滑肌细胞(VSMC)的转录途径;然而,人们对其在房颤中的作用知之甚少。鉴于AF表型转换很可能与线粒体功能和钙调神经磷酸酶有关,钙调神经磷酸酶是介导线粒体分裂和功能的HSP90客户蛋白,这项研究的目的是调查线粒体裂变是否有助于房颤的表型转换,如果确实如此,我们还旨在确定HSP90抑制作用是否能减弱线粒体裂变并随后抑制AngII诱导的高血压小鼠的房颤转化和外膜重塑。方法和结果在原发性小鼠房颤中,我们发现钙调神经磷酸酶依赖性的Drp1的去磷酸化诱导线粒体裂变并调节线粒体ROS的产生,从而刺激了AngII治疗的房颤的房颤增殖,迁移和表型转换。此外,发现AngII可以增加AF中HSP90和钙调神经磷酸酶的结合,而HSP90抑制作用则通过调节钙调神经磷酸酶依赖性的Drp1的去磷酸化作用而显着逆转AngII诱导的线粒体分裂和AF表型转换。与AFs的作用一致,在AngII诱导的外膜重塑的动物模型中,17-DMAG明显减少了线粒体裂变,AF分化,血管壁增厚和主动脉外膜的纤维化,这是由钙调神经磷酸酶/ Drp1信号传导途径介导的。结论我们的研究表明,钙调神经磷酸酶/ Drp1依赖的线粒体裂变对于理解高血压的外膜重塑可能是必不可少的,而HSP90抑制作用可能是治疗与外膜重塑相关的疾病的一种新方法。
更新日期:2020-04-17
中文翻译:
靶向HSP90通过抑制线粒体裂变来减弱血管紧张素II诱导的外膜重塑。
据报道,AIMS房室重塑表现为外膜成纤维细胞(AFs)向肌成纤维细胞(MFs)的表型转换,据报道与包括高血压在内的几种血管疾病有关。在我们之前的研究中,我们报道了热抑制蛋白90(HSP90)被17-二甲基-乙基氨基乙基氨基-17-去甲氧基格尔德霉素(17-DMAG)抑制,通过同时抑制几种关键信号传导显着减弱了血管紧张素II(AngII)诱导的腹主动脉瘤的形成。血管平滑肌细胞(VSMC)的转录途径;然而,人们对其在房颤中的作用知之甚少。鉴于AF表型转换很可能与线粒体功能和钙调神经磷酸酶有关,钙调神经磷酸酶是介导线粒体分裂和功能的HSP90客户蛋白,这项研究的目的是调查线粒体裂变是否有助于房颤的表型转换,如果确实如此,我们还旨在确定HSP90抑制作用是否能减弱线粒体裂变并随后抑制AngII诱导的高血压小鼠的房颤转化和外膜重塑。方法和结果在原发性小鼠房颤中,我们发现钙调神经磷酸酶依赖性的Drp1的去磷酸化诱导线粒体裂变并调节线粒体ROS的产生,从而刺激了AngII治疗的房颤的房颤增殖,迁移和表型转换。此外,发现AngII可以增加AF中HSP90和钙调神经磷酸酶的结合,而HSP90抑制作用则通过调节钙调神经磷酸酶依赖性的Drp1的去磷酸化作用而显着逆转AngII诱导的线粒体分裂和AF表型转换。与AFs的作用一致,在AngII诱导的外膜重塑的动物模型中,17-DMAG明显减少了线粒体裂变,AF分化,血管壁增厚和主动脉外膜的纤维化,这是由钙调神经磷酸酶/ Drp1信号传导途径介导的。结论我们的研究表明,钙调神经磷酸酶/ Drp1依赖的线粒体裂变对于理解高血压的外膜重塑可能是必不可少的,而HSP90抑制作用可能是治疗与外膜重塑相关的疾病的一种新方法。