Heart failure is a primary cause of cardiovascular morbidity and mortality with raising economic burden. There is an increasing need for innovative novel therapies. MicroRNAs are novel regulators of gene expression and are implicated in cardiac development and pathologies including heart failure. Research is underway to explore the potential of microRNA-based therapeutics. However many basic research and clinical questions remain to be solved. Dysregulation of endocannabinoid signaling has been recently described in various diseases, including heart failure. Tissue injury induces increase of endocannabinoids which, in turn is pro-apoptotic, pro-fibrogenic, promote oxidati stress and cell death. Inhibitors of the cannabinoid CB1 receptor has been proven to be vasculo- and cardioprotective. Given that microRNAs can regulate global gene networks at the translational level, it is plausible that changes in the level of bioactive molecules, such as endocannabinoid in the failing heart are associated with altered activity of specific sets of microRNA-targets. To date, the effect of endogenous or pharmacological modulators of the endocannabinoid system on cardiac microRNA expression and the potential therapeutic consequences have not been explored. The overall goals of this proposal are 1) to determine the contribution of tissue injury induced endocannabinoid activation on the cardiac microRNA expression profile that is associated with the development of heart failure, 2) to identify functionally relevant microRNAs that are sensitive to the modulation of endocannabinoid signaling and 3) to explore the therapeutic potential of the identified endocannabinoid-regulated microRNAs in heart failure development. The proposed experiments will elucidate how endocannabinoid signaling alters sets of cardiac disease-regulated microRNAs and identify endocannabinoid-sensitive miRNAs relevant for future development of microRNA-based therapeutic approaches in the treatment of heart failure