PPIA-CD147 Interaction Mediates Immune-induced Cardiomyocyte Hypertrophy After Cardiac Xenotransplantation

BACKGROUND: Pathological myocardial hypertrophy constitutes a major impediment to the prolonged survival of heart xenotransplantation. Conventional approaches, including intensive antihypertensive therapy and growth factor receptor knockout, have demonstrated limited efficacy in mitigating this maladaptive remodeling. Immune-mediated injury is the fundamental cause of xenograft failure, the intercellular communication between immune cells and cardiomyocytes remains insufficiently characterized. METHODS: To avoid confounding influences from hyperacute rejection and mechanical overload, we established an unloaded abdominal heterotopic heart xenotransplantation model using α-Gal knockout pigs to macaques. We used integrated single-cell RNA sequencing and single-nucleus RNA sequencing to investigate the immune-cardiomyocyte interaction, with and without conventional immunosuppressants. RESULTS: After xenotransplantation without immunosuppressants, cardiomyocytes demonstrated downregulation of contraction-associated gene expression. Although the administration of conventional immunosuppressants partially reinstated transcription of contraction-associated genes, their expression levels remained markedly attenuated in comparison with normal porcine myocardium. Intercellular communication analyses identified a persistent interaction between cyclophilin A (peptidylprolyl isomerase A [PPIA]) and CD147 on the cardiomyocytes, which was not fully attenuated by conventional immunosuppressants. Immunofluorescence staining confirmed the elevated membrane expression of CD147 and its colocalization with PPIA in cardiomyocytes of xenografts. In a rat-to-Balb/c heart xenotransplantation model, NIM811 (a nonimmunosuppressive extracellular PPIA inhibitor) reduced cardiomyocyte hypertrophy by 48.1%, more effectively than tacrolimus. CONCLUSIONS: The study reveals that targeting the PPIA-CD147 axis effectively mitigates immune-induced cardiomyocyte hypertrophy, offering a promising adjunctive strategy to current immunosuppressants in heart xenotransplantation.