Cardiac matrix-bound Nanovesicles provide insight into mechanisms of clinical heart disease progression to failure

Aims: Remodeling of the extracellular matrix (ECM) is critical for effective wound healing and maintaining organ homeostasis. The ECM of soft tissues, including cardiac, contains embedded nanovesicles; or matrix-bound nanovesicles (MBV). The luminal cargo of MBV consists of lipids, microRNAs (miRNAs), and proteins that influence the function of immune and stromal cells. ECM remodeling is extensive during heart disease, yet it is unknown if MBV are altered during the development of heart disease. We conducted the present study to answer this question. Methods and results: MBV were isolated from de-identified human left ventricle (LV) tissue samples from: 1) non-ischemic, failing hearts (failing) and 2) non-failing, non-ischemic hearts (control). MBV morphology was analyzed and the protein and miRNA cargo were quantified. Immunomodulatory capacity of MBV was assessed on macrophages. Failing and control heart tissue had similar concentrations of MBV, however, their size and cargo differed. MBV from failing tissue had increased levels of Apolipoprotein A-1 and decreased levels of C-Reactive Protein. Over 600 unique miRNA were detected. Of these, 5 % showed significantly different levels, with most being downregulated in MBV from failing heart tissue. Ex vivo stimulation of human macrophages with MBV isolated from control ventricular tissue, but not failing ventricles, induced gene expression suggesting increased reparative functions. Conclusion: These data reveal that MBV are present within the human heart and suggests that disease progression alters MBV cargo (lipids, microRNAs, and proteins). Furthermore, it is suggested that alterations in local MBV cargo may perpetuate pathology when their capacity to modulate reparative immune cells is diminished.