Background: Adverse cardiac remodeling following acute myocardial infarction (AMI) is one of the leading causes of mortality due to heart failure. This study aims to investigate the efficacy of GATA binding protein 4 (GATA4)-overexpressing dental pulp stem cells (GATA4-DPSCs) in mitigating post-AMI pathological remodeling by exploring their proliferative advantage, paracrine capacity, and cardiac repair potential.

Methods: H9c2 cardiomyocytes co-cultured with GATA4-DPSCs were subjected to hypoxia/reoxygenation (H/R) injury. Cell viability was assessed using Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase release assays. Oxidative stress was detected by malondialdehyde levels and flow cytometry-based reactive oxygen species. Apoptosis was evaluated by Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) staining and Western blotting, whereas cardiomyogenic differentiation markers were analyzed via Western blotting and reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Transcriptomic analysis was also performed. Rat AMI models were established. Cardiac function, myocardial injury, angiogenesis, and myocardial fibrosis markers were evaluated to assess the cardiac repair effect of transplanted GATA4-overexpressing DPSCs post-AMI. Downstream effector proteins of relevant signaling pathways were validated by Western blotting.

Results: In vitro, GATA4-DPSCs enhanced antioxidant protection from damage and reduced apoptosis in H9c2 cardiomyocytes post-H/R, while promoting their own cardiomyogenic differentiation. Multi-omics sequencing highlighted the involvement of mitogen-activated protein kinase (MAPK) pathway regulation. In vivo, GATA4-DPSCs transplantation improved cardiac function, reduced myocardial damage, enhanced angiogenesis, and ameliorated myocardial fibrosis in AMI rats. This effect correlated with downregulation of MAPK pathway effector proteins.

Conclusions: Transplantation of GATA4-overexpressing DPSCs attenuates post-AMI myocardial remodeling by modulating the MAPK signaling, ultimately mitigating fibrosis and restoring cardiac functional recovery.