Final Report Summary - ENSIG-MIRNA (Endocannabinoid signaling in heart failure: <br/>functional relevance of microRNAs) 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. Deregulation of endocannabinoid signalling 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 oxidative stress and cell death. Inhibitors of the cannabinoid CB1 receptor have been proven to be 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 endocannabinoids 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 signalling. The research outlined in this project aims to lay the foundation for new techniques to diagnose, prevent or treat the adverse cardiac remodelling during heat failure development. In summary, substantial progress has been made to understand the role of endocannabinoid signalling in myocardial interstitial fibrosis. Fibroblast-specific microRNAs have been identified and their pathogenic role in chronic cardiac remodelling has been evaluated. Some of the studies will be continued beyond the reporting period of the project. The enormous potential of microRNA-directed therapies is just being recognized. Indeed first clinical trials using microRNA inhibitors in patients with liver diseases have been recently published. The microRNA inhibitor compounds that are used in our research portfolio are generally considered as safe. The knowledge deriving from our studies are paving the way for innovative microRNA-based therapeutic approaches. The findings are relevant for future development of microRNA-based therapeutic approaches in the treatment of chronic heart failure. The project also allowed the successful re-integration of the fellow at the host institute where he became a valuable asset and greatly contributes to the expansion of the institute’s research portfolio.
