Cardiovascular disease remains the leading cause of death globally, and nearly 50% of these deaths occur due to ischemic heart disease (IHD). The Renin-Angiotensin System (RAS) has been linked to the pathology of IHD and associated risk factors, suggesting that it could be used as a therapeutic target. Exosomes are small lipid bilayer membrane extracellular vesicles (EVs) with a diameter of 30–160 nm which are known to transport miRNAs, proteins, mRNAs and other bioactive substances to the target cells. Exosomes are released in almost all physiological conditions and can impact the biological features of the recipient cells. The exosomal miRNAs are also reported to be involved in the regulation of gene expressions associated with heart failure and play an important role in cardiac remodeling. In our in silico studies, we have found that miRNA families associated with regulation of RAS pathway are present in cardiomyocyte-derived exosome cargos. But, there are no reports showing the effect of cardiomyocyte-derived exosomes in the regulation of RAS pathway under ischemic conditions. Therefore, considering this lacuna we hypothesize that ischemia will modulate the expression of cardiomyocyte-derived exosomal miRNAs, which are potentially associated with regulation of local and systemic RAS. We further hypothesize that ischemic cardiomyocyte-derived exosomes will enhance the cardioprotective effect during ischemia by modulating RAS mediated nitric oxide (NO) and reactive oxygen species (ROS) generation.The major outcome of the proposed study would be the identification of exosomal miRNA biomarkers which are associated with the regulation of RAS pathway during myocardial ischemia. In the near future, exosomes could be used to improve cardiac function in people with progressive heart failure.The findings from this study may provide new therapeutic approaches to target RAS pathway during myocardial injury.