Canonical Transient Receptor Potential Channel 1 Aggravates Myocardial Ischemia-and-reperfusion Injury by Upregulating Reactive Oxygen Species

The canonical transient receptor potential channel (TRPC) proteins form Ca-permeable cation channels that are involved in various heart diseases. However, the roles of specific TRPC proteins in myocardial ischemia/reperfusion (I/R) injury remain poorly understood. We observed that TRPC1 and TRPC6 were highly expressed in the area at risk (AAR) in a coronary artery ligation induced I/R model. mice exhibited improved cardiac function, lower serum Troponin T and serum creatine kinase level, smaller infarct volume, less fibrotic scars, and fewer apoptotic cells after myocardial-I/R than wild-type or mice. Cardiomyocyte-specific knockdown of using adeno-associated virus 9 mitigated myocardial I/R injury. Furthermore, deficiency protected adult mouse ventricular myocytes (AMVMs) and HL-1 cells from death during hypoxia/reoxygenation (H/R) injury. RNA-sequencing-based transcriptome analysis revealed differential expression of genes related to reactive oxygen species (ROS) generation in cardiomyocytes. Among these genes, oxoglutarate dehydrogenase-like () was markedly downregulated. Moreover, deficiency impaired the calcineurin (CaN)/nuclear factor-kappa B (NF-κB) signaling pathway in AMVMs. Suppression of this pathway inhibited upregulation and ROS generation in HL-1 cells under H/R conditions. Chromatin immunoprecipitation assays confirmed NF-κB binding to the promoter. The cardioprotective effect of deficiency was canceled out by overexpression of and in cardiomyocytes. In conclusion, our findings reveal that TRPC1 is upregulated in the AAR following myocardial I/R, leading to increased Ca influx into associated cardiomyocytes. Subsequently, this upregulates expression through the CaN/NF-κB signaling pathway, ultimately exacerbating ROS production and aggravating myocardial I/R injury.