Tagashira Hideaki, Bhuiyan Md Shenuarin, Shinoda Yasuharu, Kawahata Ichiro, Numata Tomohiro, Fukunaga Kohji
Department of Integrative Physiology, Graduate School of Medicine, Akita University, Akita, Japan; Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA.
J Pharmacol Sci. 2023 Feb;151(2):128-133. doi: 10.1016/j.jphs.2022.12.005. Epub 2022 Dec 19.
The Sigma-1 receptor (Sigmar1) is downregulated in heart failure model mice with mitochondrial dysfunction. However, the mechanism in detail has not been investigated. In this study, we investigated the role of Sigmar1 in ER-mitochondria proximity using Sigmar1-knockdown or -overexpressed neonatal rat ventricular myocytes (NRVMs). The endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy was aggravated with the dysregulation of mitochondrial function and ER-mitochondrial junctional formation in Sigmar1-knockdown NRVMs, whereas improved in Sigmar1 overexpressed NRVMs. Our data suggests that the reduction of the cardiac Sigmar1 results in decrease mitochondrial Ca influx and promotes mitochondrial fission, followed by reduced ER-mitochondria proximity, exacerbating ET-1-induced cardiomyocyte injury.
在伴有线粒体功能障碍的心力衰竭模型小鼠中，西格玛-1受体（Sigmar1）表达下调。然而，其具体机制尚未得到研究。在本研究中，我们利用西格玛-1基因敲低或过表达的新生大鼠心室肌细胞（NRVMs），研究了Sigmar1在内质网-线粒体接近中的作用。在内皮素-1（ET-1）诱导的心肌细胞肥大中，Sigmar1基因敲低的NRVMs中线粒体功能失调和内质网-线粒体连接形成受损，而Sigmar1过表达的NRVMs中上述情况得到改善。我们的数据表明，心脏Sigmar1减少会导致线粒体钙内流减少并促进线粒体分裂，进而使内质网-线粒体接近度降低，加重ET-1诱导的心肌细胞损伤。
