PRMT1 inhibition enhances the cardioprotective effect of adipose-derived mesenchymal stem cells against myocardial infarction through RUNX1.

BACKGROUND: The poor viability and paracrine function of transplanted mesenchymal stem cells (MSCs) hamper their therapeutic efficacy in ischemic heart injury treatment. Protein arginine methyltransferases (PRMTs) mediate arginine methylation and have important functions in cellular responses. However, the role of PRMTs in MSC-based therapies for ischemic heart injury remains unclear. The aim of this study was to investigate the effect of PRMT1 on MSC function and therapeutic efficacy using a mouse myocardial infarction (MI) model. METHODS: We isolated, cultured, and identified mouse adipose tissue-derived mesenchymal stromal cells (ADSCs). We used Furamidine, a PRMT1 inhibitor, and adenoviral shPRMT1 to study the effects of PRMT1 inhibition on ADSC proliferation, migration, and viability. We performed RNA sequencing and biochemical experiments to elucidate the molecular mechanisms of PRMT1 in ADSCs. Finally, we infected ADSCs with adenoviral shPRMT1 and administered an intramyocardial injection after MI. Cardiac function was evaluated using echocardiography and pathological staining, and ADSCs survival rates, cardiomyocyte apoptosis, and capillary density were evaluated using immunofluorescence staining. RESULTS: We found that PRMT1 was highly expressed in ADSCs and markedly upregulated in response to H(2)O(2) challenge. Inhibition of PRMT1 by Furamidine or adenoviral shPRMT1 promoted ADSC proliferation and migration and reduced H(2)O(2)-induced ADSCs apoptosis. Mechanistically, PRMT1 inhibition significantly increased the expression of matrix metallopeptidase (MMP)-10, placenta growth factor (PlGF) and transforming growth factor (TGF)-β2 in ADSCs through transcription factor RUNX1. Blockage of RUNX1 abolished the proliferative and migratory effects of PRMT1 inhibition in ADSCs. Compared to ADSCs infected with the adenovirus-control, PRMT1 knockdown adenovirus markedly increased the survival and retention of transplanted ADSCs in injured hearts after MI. ADSCs with PRMT1 knockdown markedly improved cardiac function and alleviated cardiac fibrosis in mice after MI by reducing cardiomyocyte apoptosis and increasing capillary density. CONCLUSIONS: PRMT1 inhibition enhances the cardioprotective effect of ADSCs against MI through RUNX1-mediated production of MMP-10/PlGF/TGF-β2. Overall, PRMT1 inhibition is a promising strategy for augmenting MSCs therapeutic efficacy in ischemic cardiomyopathy.