Alteration Of Left Ventricular Load Impacts Exosomal And Cardiac MicroRNA Expression In A Porcine Model Of Myocardial Ischemia

Background: Mechanical unloading of the left ventricle (LV) after myocardial infarction (MI) exhibits cardioprotective effects. The underlying molecular mechanisms of these benefits are not fully elucidated. MicroRNAs (miRNA) are vital regulators of cellular processes. When released into circulation within exosomes, they participate in inter and intra-organ communications. We hypothesized that LV load influences exosomal and myocardial miRNA expression. Methods: Anterior MI was induced in Yorkshire pigs. After one week, pigs underwent mechanical LV unloading per Impella or LV overloading by percutaneous aortic valve destruction (n = 5 each). Two hours later, coronary sinus blood was collected, animals were euthanized and infarct border zone tissue was harvested. Exosomal miRNAs isolated from blood were studied using next-generation sequencing. Myocardial tissue expression of select differentially regulated exosomal miRNAs was assessed by quantitative PCR. Results: In coronary sinus blood from LV unloaded animals exosomal miR-19b, miR-20a, miR-21, miR-144, and miR-146b showed higher expression compared to LV overloaded pigs (log2 FC = 3.47, 2.64, 1.86, 2.62, 1.58; p<0.05). Opposite relationships were observed in myocardial tissue. MiR-19b and miR-20a showed lower expression in LV unloaded compared to overloaded animals (FC = 0.36 ± 0.11 and 0.37 ± 0.12, p<0.05). A similar trend was found for miR-21, miR-144, and miR-146b expression. Conclusion: Exosomal miRNAs in coronary sinus blood are affected by changes in LV load. Inverse expression patterns in myocardial tissue suggest increased cardiac release or decreased uptake of exosomes as a possible mechanism.