Department of Cardiology, Beijing AnZhen Hospital, Capital Medical University, Beijing, China.
Emergency and Critical Care Center, Beijing Anzhen Hospital, Capital Medical University, China.
Cell Biochem Funct. 2020 Jul;38(5):549-557. doi: 10.1002/cbf.3503. Epub 2020 Feb 10.
Neuregulin-1 (NRG-1)/erythroblastic leukaemia viral oncogene homologues (ErbB) pathway activation plays a crucial role in regulating the adaptation of the adult heart to physiological and pathological stress. In the present study, we investigate the effect of recombined human NRG-1 (rhNRG-1) on mitochondrial biogenesis, mitochondrial function, and cell survival in neonatal rat cardiac myocytes (NRCMs) exposed to hypoxia/reoxygenation (H/R). The results of this study showed that, in the H/R-exposed NRCMs, mitochondrial biogenesis was impaired, as manifested by the decrease of the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and mitochondrial membrane proteins, the inner membrane (Tim23), mitofusin 1 (Mfn1), and mitofusin 2 (Mfn2). RhNRG-1 pretreatment effectively restored the expression of PGC-1α and these membrane proteins, upregulated the expression of the anti-apoptosis proteins Bcl-2 and Bcl-xL, preserved the mitochondrial membrane potential, and attenuated H/R-induced cell apoptosis. Blocking PGC-1 expression with siRNA abolished the beneficial role of rhNRG-1 on mitochondrial function and cell survival. The results of the present study strongly suggest that NRG-1/ErbB activation enhances the adaption of cardiomyocytes to H/R injury via promoted mitochondrial biogenesis and improved mitochondrial homeostasis. SIGNIFICANCE OF THE STUDY: The results of this research revealed for the first time the relationship between neuregulin-1 (NRG-1)/erythroblastic leukaemia viral oncogene homologues (ErbB) activation and mitochondrial biogenesis in neonatal cardiomyocytes and verified the significance of this promoted mitochondrial biogenesis in attenuating hypoxia/reoxygenation injury. This finding may open a new field to further understand the biological role of NRG-1/ErbB signalling pathway in cardiomyocyte.
神经调节蛋白-1（NRG-1）/红细胞白血病病毒癌基因同源物（ErbB）通路的激活在调节成年心脏适应生理和病理应激方面起着至关重要的作用。在本研究中，我们研究了重组人 NRG-1（rhNRG-1）对缺氧/复氧（H/R）暴露的新生大鼠心肌细胞（NRCM）中线粒体生物发生、线粒体功能和细胞存活的影响。本研究结果表明，在 H/R 暴露的 NRCM 中，线粒体生物发生受损，表现为过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）和线粒体膜蛋白的表达减少，内膜（Tim23）、融合蛋白 1（Mfn1）和融合蛋白 2（Mfn2）。rhNRG-1 预处理可有效恢复 PGC-1α 和这些膜蛋白的表达，上调抗凋亡蛋白 Bcl-2 和 Bcl-xL 的表达，维持线粒体膜电位，减轻 H/R 诱导的细胞凋亡。用 siRNA 阻断 PGC-1 的表达可消除 rhNRG-1 对线粒体功能和细胞存活的有益作用。本研究结果强烈表明，NRG-1/ErbB 激活通过促进线粒体生物发生和改善线粒体稳态来增强心肌细胞对 H/R 损伤的适应能力。本研究的意义：这项研究首次揭示了神经调节蛋白-1（NRG-1）/红细胞白血病病毒癌基因同源物（ErbB）激活与新生心肌细胞中线粒体生物发生之间的关系，并验证了这种促进的线粒体生物发生在减轻缺氧/复氧损伤中的重要性。这一发现可能为进一步了解 NRG-1/ErbB 信号通路在心肌细胞中的生物学作用开辟新的领域。
