MicroRNA-221/222 Mediates ADSC-Exosome-Induced Cardioprotection Against Ischemia/Reperfusion by Targeting PUMA and ETS-1

Abstract

Cardiovascular disease is a major health problem in industrialized and developing countries and is the leading cause of death and disability. Myocardial ischemia/reperfusion (I/R) causes cardiomyocyte damage such as apoptosis and hypertrophy. The purpose of this study was to investigate the effects of exosomes from adipose-derived stem cells (ADSC-Exo) on hearts from I/R mice and to explore the underlying mechanisms. ADSC-Exo significantly decreased I/R-induced cardiomyocyte apoptosis and hypertrophy, as detected by TdT-mediated dUTP nick end-labeling (TUNEL) and wheat germ agglutinin (WGA) staining, respectively. In addition, the expression of apoptosis-related proteins p-p53 and PUMA and hypertrophy-related proteins ETS-1 and ANP were significantly reduced in the cardiomyocytes of ADSC-Exo-treated I/R mice compared to those of control mice. Both PUMA and ETS-1 are reported to be target genes for miR-221/222. I/R operation significantly reduced miR-221/222 expression, while ADSC-Exo treatment increased miR-221/222 expression, as detected by RT-qPCR. We also observed that cardiac I/R operation markedly increased cell apoptosis and hypertrophy in miR-221/222 knockout (KO) mice, while ADSC-Exo reduced the effects of I/R operation. Furthermore, ADSC-Exo protected H9c2 cardiomyocytes from H2O2-induced damage by reducing apoptosis and hypertrophy in vitro. H2O2 treatment significantly reduced miR-221/222 expression, while ADSC-Exo treatment reversed this effect in H9c2 cells. ADSC-Exo treatment decreased H2O2-induced PUMA and ETS-1 expression. Compared with control treatment, I/R treatment significantly reduced p-AKT and increased p-p65, while ADSC-Exo and miR-221/222 mimics attenuated these effects. The AKT activator SC79 and p65 inhibitor Bay 11-7082 reduced H2O2-induced cell apoptosis and hypertrophy. Based on these findings, ADSC-Exo prevents cardiac I/R injury through the miR-221/miR-222/PUMA/ETS-1 pathway. Therefore, ADSC-Exo is an effective inhibitor of I/R-induced heart injury.

Propofol Ameliorates Microglia Activation by Targeting MicroRNA-221/222-IRF2 Axis

“…Moreover, we found that the miR-221/222-IRF2 axis is a functional mediator of the anti-inflammatory roles of propofol. However, several other molecular targets of miR-221/222 have been reported, such as Notch3 [ 27 ], CACNA1C and KCNJ5 [ 41 ], PUMA and ETS-1 [ 42 ], and genes involved in inflammatory response (ETS1/2, IRF2, BCL2L11, TOX, BMF, and CXCL12) [ 43 ], and whether these targets are involved in the anti-inflammatory roles of propofol in microglia remains an area of active study. Notably, miRNA-based therapies for disease treatments are under rapid clinical development [ 24 ]; targeting mir-221/222 may provide innovative practical therapeutics for patients with traumatic brain injury and ischemic stroke.…”

Potential Applications and Functional Roles of Exosomes in Cardiometabolic Disease

“…Ischemia-reperfusion injury is a hallmark of myocardial infarction, and it is a potent factor that increases exosome release in bone marrow-derived dendritic cells and macrophages [112]. In an inflammatory environment, dendritic cells downregulate the immune response by increasing the differentiation of CD4+ T cells into a Foxp3+ Treg antiinflammatory phenotype via exosome signaling [113,114]. Exosomal HP70 also released by dendritic cells stimulates the PI3K/mTOR axis regulating Treg and Th17 cell differentiation and attenuating ischemia-reperfusion injury [113].…”

Exosomal Non-Coding RNAs: Regulatory and Therapeutic Target of Hepatocellular Carcinoma

“…For example, myelin oligodendrocytes count on exosomal secretion to promote axon transport and long axon maintenance in adjacent neurons (28). Adipose stem cell-derived exosomes inhibit ischemia-reperfusion injury of cardiomyocytes by targeting miR-221/miR-222/PUMA/ETS proto-oncogene 1 (ETS-1) pathway (29). Exosomal Hic-5 regulates the proliferation and apoptosis of osteosarcoma via Wnt/b-catenin signal pathway (30).…”