KAT2A-targeted inhibition prevents an inflammatory response to protect the myocardium

Background: Hyperactive inflammation is crucial for the development of acute myocardial infarction (AMI) to heart failure and can promote impaired cardiac function, and it is difficult to determine its specific therapeutic targets and drugs. Therefore, it is necessary to develop new therapeutic strategies to control inflammatory responses to protect myocardial cells during AMI. Methods: Levels of critical cardiac markers and inflammatory factors were measured in blood samples collected from clinical patients with AMI to analyze the association between the serum expression levels of inflammatory factors and the progression of AMI. To uncover the mechanism underlying the association between inflammatory response and AMI, microarray analysis was performed to identify key myocardial cell regulators. ATAC-seq was also performed to identify how immune response genes are transcriptionally regulated by KAT2A. KAT2A -/- genetically engineered mice were used to validate the screened targets. Finally, a small molecule targeting KAT2A was developed and tested in a rat model of AMI. Results: Here we show that KAT2A, a histone H3K9 acetyltransferase, is a key factor regulating the inflammatory response in AMI. Specifically, the level of cardiac damage was initially found to be associated with the inflammatory response in patients with AMI. Regarding the mechanism, KAT2A transcriptionally regulates pro-inflammatory tumor necrosis factor alpha and interleukin-6 to induced cardiomyocyte damage. Using a genetically engineered mouse model of AMI, we show that targeted KAT2A loss or inhibition prevents the recruitment of immune cells into the myocardium to suppress the inflammatory explosion in AMI in vivo and significantly improved heart function. Finally, Tanshinone I, a KAT2A-targeted inhibitor, could inhibited the inflammatory response in AMI in vivo. Conclusion: KAT2A is a potential therapeutic target for AMI, especially for inhibiting the inflammatory response to this condition. As a specific KAT2A-targeted inhibitor, Tanshinone I is a potent candidate drug for AMI.