Age and Sex-Dependent Differences in Human Cardiac Matrix-Bound Exosomes Modulate Fibrosis through Synergistic miRNA Effects

Aging is a risk factor for cardiovascular disease, the leading cause of death worldwide. Cardiac fibrosis is a harmful result of repeated myocardial infarction that increases risk of morbidity and future injury. Interestingly, rates of cardiac fibrosis are different between young and aged individuals, as well as men and women. Here, for the first time, we identify and isolate matrix-bound extracellular vesicles from the left ventricles (LVs) of young or aged men and women. These LV vesicles (LVVs) show differences in morphology and content between these four cohorts. LVVs effects on fibrosis were also investigated in vitro, and it was shown that aged male LVVs were pro-fibrotic, while other LVVs were anti-fibrotic. miRNAs identified from these LVVs could partially recapitulate these effects together, but not individually, and confer other benefits. These data suggest that synergistic effects of matrix-resident exosomal miRNAs may influence the differential clinical response to MI.