Cardiac miRNAs Contribute to Cognitive Impairment by Extracellular Vesicles Following Myocardial Injury

PROJECT SUMMARY/ABSTRACT Cognitive impairment (CGI) is prevalent and affects 20-80% of patients with heart failure (HF). However, the underlying mechanisms linking heart injury to cognitive impairment are not yet well understood. Although a HF-induced brain injury may be multifunctional, neuroinflammation is being increasingly recognized as a common feature of CGI. Recently, miRNA-enriched extracellular vesicles (EVs) have emerged as regulators of intra- and inter-organ communications during pathophysiological processes in the cardiovascular system. Our long- term goal is to better define the mechanism by which EV-mediated heart-brain communication provokes neuroinflammation following myocardial infarction (MI). Our previous studies showed the involvement of miRNAs and EVs in disrupting the redox homeostasis of the brain stem in HF. These findings led to the central hypothesis that myocardial injury boosts the secretion of miRNA-enriched EVs from cardiac cells, which circulate into brain regions and then promote neuroinflammation and neurotoxicity by entering glial cells and neurons, respectively, contributing to accelerated CGI. We have identified miRNA-21-5p, which was selectively upregulated in cardiac cells and immune cells and then secreted into extracellular space by EVs. The preliminary data also demonstrated the brain distribution and glial uptakes of cardiac EVs and the upregulation of miR-21-5p in brain-isolated EVs, which may be responsible for neuroinflammation and neurotoxicity. Guided by this strong preliminary data, the team proposes two Specific Aims: 1) To investigate whether cardiac miRNA-enriched EVs contribute to neuroinflammation and neurotoxicity following MI, and 2) To determine how cardiac miRNA- enriched EVs participate in heart-brain communication contributing to neuroinflammation and CGI in HF and to further identify the potential targets contributing to glial activation and subsequent neuronal dysfunctions. The proposed research is innovative because it pursues the novel idea that cardiac-derived miRNA-enriched EVs contribute to increased neuroinflammation in the HF state. This proposed study will clearly demonstrate a direct heart-brain crosstalk via EVs, and further elucidate the potential mechanism by which the damaged heart communicates with the brain, thus contributing to neuroinflammation and promoting subsequent CGI following MI. Importantly, this project will further provide a new therapeutic target and novel methods of managing CGI during HF.