The Key Laboratory of Fujian Province Universities on Ion Channel and Signal Transduction in Cardiovascular Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China.
The Key Laboratory of Fujian Province Universities on Ion Channel and Signal Transduction in Cardiovascular Diseases, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China; Department of Physiology and Pathophysiology, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China.
Toxicol Appl Pharmacol. 2023 Jul 1;470:116547. doi: 10.1016/j.taap.2023.116547. Epub 2023 May 11.
Daunorubicin (DNR-) induced cardiotoxicity seriously restricts its clinical application. Transient receptor potential cation channel subfamily C member 6 (TRPC6) is involved in multiple cardiovascular physiological and pathophysiological processes. However, the role of TRPC6 anthracycline-induced cardiotoxicity (AIC) remains unclear. Mitochondrial fragmentation greatly promotes AIC. TRPC6-mediated ERK1/2 activation has been shown to favor mitochondrial fission in dentate granule cells. The aim of the present study was to elucidate the effects of TRPC6 on daunorubicin- induced cardiotoxicity and identify the mechanisms associated with mitochondrial dynamics. The sparkling results showed that TRPC6 was upregulated in models in vitro and in vivo. TRPC6 knockdown protected cardiomyocytes from DNR-induced cell apoptosis and death. DNR largely facilitated mitochondrial fission, boosted mitochondrial membrane potential collapse and damaged debilitated mitochondrial respiratory function in H9c2 cells，these effects were accompanied by TRPC6 upregulation. siTRPC6 effectively inhibited these mitochondrial adverse aspects showing a positive unexposed effect on mitochondrial morphology and function. Concomitantly, ERK1/2-DRP1 which is related to mitochondrial fission was significantly activated with amplified phosphorylated forms in DNR-treated H9c2 cells. siTRPC6 effectively suppressed ERK1/2-DPR1 over activation, hinting at a potential correlation between TRPC6 and ERK1/2-DRP1 by which mitochondrial dynamics are possibly modulated in AIC. TRPC6 knockdown also raised the Bcl-2/Bax ratio, which may help to block mitochondrial fragmentation-related functional impairment and apoptotic signaling. These findings suggested an essential role of TRPC6 in AIC by intensifying mitochondrial fission and cell death via ERK1/2-DPR1, which could be a potential therapeutic target for AIC.
柔红霉素（DNR）诱导的心脏毒性严重限制了其临床应用。瞬时受体电位阳离子通道亚家族 C 成员 6（TRPC6）参与多种心血管生理和病理生理过程。然而，TRPC6 与蒽环类药物诱导的心脏毒性（AIC）的关系尚不清楚。线粒体片段化极大地促进了 AIC。已经表明，TRPC6 介导线粒体 ERK1/2 的激活有利于齿状回颗粒细胞中的线粒体裂变。本研究旨在阐明 TRPC6 对柔红霉素诱导的心脏毒性的影响，并确定与线粒体动力学相关的机制。令人瞩目的结果表明，TRPC6 在体外和体内模型中均上调。TRPC6 敲低可保护心肌细胞免受 DNR 诱导的细胞凋亡和死亡。DNR 可显著促进线粒体裂变，增加线粒体膜电位崩溃，并损害 H9c2 细胞中受损的线粒体呼吸功能，这些作用伴随着 TRPC6 的上调。siTRPC6 有效地抑制了这些线粒体的不良方面，对线粒体形态和功能表现出积极的未暴露效应。同时，与线粒体裂变相关的 ERK1/2-DRP1 在 DNR 处理的 H9c2 细胞中显著激活，并表现出放大的磷酸化形式。siTRPC6 有效地抑制了 ERK1/2-DPR1 的过度激活，表明 TRPC6 与 ERK1/2-DPR1 之间可能存在潜在的相关性，通过这种相关性可能调节 AIC 中的线粒体动力学。TRPC6 敲低还提高了 Bcl-2/Bax 比值，这可能有助于阻断与线粒体片段化相关的功能障碍和凋亡信号。这些发现表明，TRPC6 通过 ERK1/2-DPR1 增强线粒体裂变和细胞死亡在 AIC 中起着重要作用，这可能成为 AIC 的潜在治疗靶点。
