Mitochondrial fission inhibition protects against hypertension induced by angiotensin II.
Mitochondrial fission inhibition protects against hypertension induced by angiotensin II.
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DOI：
10.1038/s41440-024-01610-0
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发表时间：
2024-02
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通讯作者：
Kyle J. Preston;Tatsuo Kawai;Keiichi Torimoto;R. Kuroda;Yuki Nakayama;Tomoko Akiyama;Y. Kimura;Rosario Scalia;Michael V Autieri;Victor Rizzo;Tomoki Hashimoto;Patrick Osei-Owusu;Satoru Eguchi
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作者：
Kyle J. Preston;Tatsuo Kawai;Keiichi Torimoto;R. Kuroda;Yuki Nakayama;Tomoko Akiyama;Y. Kimura;Rosario Scalia;Michael V Autieri;Victor Rizzo;Tomoki Hashimoto;Patrick Osei-Owusu;Satoru Eguchi
线粒体功能障碍与包括高血压在内的各种心血管疾病有关。线粒体裂变融合平衡对线粒体质量控制至关重要，而在几种心血管疾病模型中已报道了增强的裂变。然而，关于线粒体分裂在高血压中的作用的信息有限。在这里，我们已经测试了抑制线粒体分裂减弱高血压和相关血管重塑的发展的假设。在C57 BL 6小鼠中，血管紧张素II输注2周，线粒体裂变抑制剂mdiv 1的联合治疗，显著抑制血管紧张素II诱导的高血压的发展，通过无线电遥测评估。心脏和动脉的组织学评估表明，mdiv 1抑制血管紧张素II诱导的血管纤维化和肥大。这与血管紧张素II诱导的线粒体纵横比下降的衰减有关，见于血管内皮和中层。通过心脏重量/体重比和超声心动图评估，Mdivi 1还减轻了血管紧张素II诱导的心脏肥大。在离体实验中，mdiv 1抑制血管收缩，并取消血管紧张素II在小肠系膜动脉血管反应性增强。对血管紧张素II和/或mdiv 1处理的内皮细胞培养基的蛋白质组学分析显示，mdiv 1抑制血管紧张素II诱导的内皮细胞高分泌表型。此外，mdivi 1减弱血管紧张素II诱导的骨膜蛋白（培养的血管成纤维细胞中的肌成纤维细胞标记物）的蛋白诱导。总之，这些数据表明，mdiv 1通过血管系统中的多细胞机制预防血管紧张素II诱导的高血压和心血管重塑。
Mitochondrial dysfunction has been implicated in various types of cardiovascular disease including hypertension. Mitochondrial fission fusion balance is critical to mitochondrial quality control, whereas enhanced fission has been reported in several models of cardiovascular disease. However, limited information is available regarding the contribution of mitochondrial fission in hypertension. Here, we have tested the hypothesis that inhibition of mitochondrial fission attenuates the development of hypertension and associated vascular remodeling. In C57BL6 mice infused with angiotensin II for 2 weeks, co-treatment of mitochondrial fission inhibitor, mdivi1, significantly inhibited angiotensin II-induced development of hypertension assessed by radiotelemetry. Histological assessment of hearts and aortas showed that mdivi1 inhibited vessel fibrosis and hypertrophy induced by angiotensin II. This was associated with attenuation of angiotensin II-induced decline in mitochondrial aspect ratio seen in both the endothelial and medial layers of aortas. Mdivi1 also mitigated angiotensin II-induced cardiac hypertrophy assessed by heart weight-to-body weight ratio as well as by echocardiography. In ex vivo experiments, mdivi1 inhibited vasoconstriction and abolished the enhanced vascular reactivity by angiotensin II in small mesenteric arteries. Proteomic analysis on endothelial cell culture media with angiotensin II and/or mdivi1 treatment revealed that mdivi1 inhibited endothelial cell hypersecretory phenotype induced by angiotensin II. In addition, mdivi1 attenuated angiotensin II-induced protein induction of periostin, a myofibroblast marker in cultured vascular fibroblasts. In conclusion, these data suggest that mdivi1 prevented angiotensin II-induced hypertension and cardiovascular remodeling via multicellular mechanisms in the vasculature.