Nynrin enhances cardiac function by inhibiting mitochondrial permeability transition pore opening upon myocardial...

Acute myocardial infarction (AMI) is a leading cause of cardiovascular disease-related death. Reperfusion therapies, although essential, can exacerbate damage through myocardial ischemia/reperfusion (I/R) injury. Cyclophilin D (CypD) and mitochondrial permeability transition pore (mPTP) opening have been identified as potential therapeutic targets for I/R injury. However, clinical trials with cyclosporin A (CsA) have shown mixed results, highlighting the urgent need for alternative strategies to suppress CypD expression or activity. In this study, we explored the role of Nynrin, a newly identified transcriptional repressor of peptidylprolyl isomerase F (Ppif) that encodes CypD, in mitigating I/R injury by regulating mPTP opening. We first observed that Nynrin was downregulated in adult mouse hearts subjected to I/R and in primary adult mouse cardiomyocytes upon oxygen-glucose deprivation/reperfusion (OGD/R). Subsequently, we generated a tamoxifen-inducible cardiomyocyte-specific Nynrin-knockout (Nynrin-cKO) mouse model, which was well-tolerated in otherwise normal adult mouse hearts. Notably, Nynrin-cKO mice exhibited exacerbated contractile dysfunction and cardiac injury, characterized by enhanced Ppif transcription, CypD expression, mPTP opening, and cardiomyocyte death when subjected to I/R. Furthermore, the exacerbated I/R-induced cardiac dysfunction in Nynrin-cKO mice was significantly reversed by CsA, an mPTP inhibitor that targets CypD, indicating that the intensified pathological manifestations in Nynrin-cKO mice during I/R injury were dependent on CypD and mPTP. Conversely, Nynrin overexpression in primary adult mouse cardiomyocytes blunted Ppif/CypD upregulation and restrained mPTP opening, thus reducing cardiomyocyte damage upon OGD/R. Taken together, our findings highlight the critical role of Nynrin in regulating CypD and mPTP in I/R injury and suggest that targeting Nynrin may be a promising therapeutic strategy for mitigating cardiac dysfunction in managing I/R injury.