TRPC6 promotes daunorubicin-induced mitochondrial fission and cell death in rat cardiomyocytes with the involvement of ERK1/2-DRP1 activation.

Abstract

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.

• Authors: Li-Xia Xu, Rui-Xing Wang, Jian-Feng Jiang, Gao-Cheng Yi, Jin-Jin Chang, Rui-Lan He, Hai-Xia Jiao, Bin Zheng, Long-Xin Gui, Jun-Jin Lin, Zhi-Hong Huang, Mo-Jun Lin, Zhi-Juan Wu
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 470 Pg. 116547 (07 01 2023) ISSN: 1096-0333 [Electronic] United States
• PMID: 37178933 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• Daunorubicin
• Dynamins
• TRPC Cation Channels
• TRPC6 Cation Channel
• Trpc6 protein, rat
• Dnm1l protein, rat

Topics

• Animals
• Rats
• Apoptosis
• Cardiotoxicity (metabolism)
• Cell Death
• Daunorubicin (toxicity)
• Dynamins (metabolism)
• MAP Kinase Signaling System
• Mitochondrial Dynamics
• Myocytes, Cardiac (metabolism)
• TRPC Cation Channels (genetics, metabolism)
• TRPC6 Cation Channel (metabolism)