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Background and Purpose Myocardial infarction (MI) is one of the leading causes of death worldwide. Following MI, adverse cardiac remodelling involving cell death/apoptosis, hypertrophy and fibrosis, plays major role in the process leading to heart failure.Our previous study has identified Salt-inducible kinase 2 (SIK2) as an important inducer of pathological remodelling in a model of MI. We found that SIK2 KO mice exhibited significantly reduced infarct size and fibrosis following myocardial infarction via modulation of Yes-associated protein (YAP), suggesting that the absence of SIK2 may confer a cardioprotective effect. These findings led us to hypothesise that pharmacological inhibition of SIK2 protects the heart from adverse remodelling following MI.Methods We used H9C2 cell line to screen several SIKs inhibitor (HG-9 91-01, GLPG3321, YKL-05-099, YKL-06-061, ARN-3236) that can effectively modulate YAP activity. Confirmation assay was performed using neonatal rat cardiomyocytes (NRCM).For the in vivo model, 12-weeks old wildtype C57BL/6 mice were subjected to MI with or without treatment with SIK inhibitor. Cardiac phenotypes were assessed by echocardiography, and at the end of the treatment, heart tissue was collected for histology analysis.Results Screening of several SIKs inhibitor in vitro identified ARN-3236 as the most potent enhancer of YAP activity in H9C2 cells. Confirmatory analysis using NRCMs showed that ARN-3236 at a concentration of 1 µM significantly enhanced YAP-luciferase activity, and reduced apoptosis following oxidative stress (H 2O2 treatment) (p-value 0.0034). However, there was no considerable effect observed on cell proliferation rate (Ki-67 staining).In vivo study revealed that injection with ARN-3236 (1 mg/kgBW) every day for 10 days resulted in a trend of improvement in cardiac function following MI. We observed a trend of higher ejection fraction (EF) in ARN-3236 treated mice compared to the non-treated group after MI (p-value 0.0789). However, ARN-3236 did not improve diastolic function as indicated by the measurements of E/E’ and E/A values. We also assessed wall thickness following MI and found no significant differences between the ARN-3236 and control groups.We analysed infarct size using Masson’s trichrome staining of cardiac tissue sections. Although on average mice treated with ARN-3236 displayed 36% less infarct size compared to control, it did not reach statistical significance. Furthermore, there was no change in cellular hypertrophic response as indicated by analysis of cardiomyocyte size. However, ARN-3236 treatment significantly reduced apoptosis level as demonstrated by marked reduction in TUNEL positive cardiomyocytes (p-value 0.0015), a result that was consistent with our previous finding using SIK2 KO mice.Conclusion Treatment with ARN-3236, a selective SIK2 inhibitor, might produce beneficial effects in mouse model of MI, possibly through inhibition of apoptosis. Further studies are needed to understand the molecular mechanisms underlying this finding.