Introduction: Arginine methylation has emerged as a key post-translational modification as prevalent as phosphorylation in mammals owing to generation of new methylarginine antibodies, advanced proteomic techniques, specific pharmacological inhibitors and new transgenic models. Among the nine protein-arginine-methyltransferases (PRMTs), PRMT5 is the major symmetric dimethylation enzyme. It plays crucial roles in cell proliferation, differentiation and cell cycle control by versatile mechanisms including chromatin/histone modification, ribosome biogenesis and transcriptional suppression of tumor suppressor genes. PRMT5 is robustly expressed in the heart. We assessed PRMT5 functions in the heart after injury.
Methods: Mouse ischemic injury was induced by coronary artery ligation and heart function and morphology were assessed. PRMT5 inhibitor EPZ015666 (or vehicle) were given to mice by gavage. Vessel density and fibrosis were measured by CD31 and Sirius red respectively.
Results: We found that PRMT5 is significantly induced in the epicardium of the heart after myocardial infarction. The MI-induced PRMT5 expression emerged within a day, peaked around day 3-5, and vanished at day 7 post injury. To investigate the functional significance of this acute PRMT5 induction, we administered EPZ015666, a potent and specific PRMT5 inhibitor, to mice for 3-5 days after MI. We found that vessel density was significantly lower in EPZ015666-treated mouse hearts, especially in the border zone of infarction. Ejection function was also lower in EPZ015666-treated mice compared to vehicle group.
Conclusions: Acutely induction of PRMT5 in the epicardium is a cardiac protective mechanism following injury. How the acute activation of epicardial PRMT5 modulates neovascularization and myocardial function to protect the heart and what methylation targets mediate the effects are currently under extensive investigation. Cardiac toxicity is one of the major concerns for cancer therapies. EPZ015666 is in preclinical testing for lymphoma treatment. Our findings highlight the caution of EPZ015666 usage for patients with cardiovascular complications.