Serum-Derived Extracellular Vesicles Protect Against Acute Myocardial Infarction by Regulating miR-21/PDCD4 Signaling Pathway

Abstract

Acute myocardial infarction (AMI) represents a leading cause of morbidity and mortality worldwide. Extracellular vesicles (EVs) are being recognized as a promising therapeutic approach in protecting against MI. Serum is a rich source of EVs, which transports various microRNAs (miRNAs, miRs). EVs from serum have been shown beneficial for protecting against ischemia-reperfusion injury; however, their roles in AMI are unclear. In addition, whether a miRNA might be responsible for the effects of serum EVs on protecting against AMI is undetermined. Here, we demonstrated that serum EVs significantly reduced cardiomyocytes apoptosis in both cellular and mouse models of AMI, and dramatically attenuated the infarct size in mouse hearts after AMI. Inhibition of miR-21 was shown to reduce the protective effects of serum EVs in inhibiting cardiomyocytes apoptosis. miR-21 was decreased in mouse hearts after AMI, while serum EVs increased that. In addition, the programmed cell death 4 (PDCD4) expression was identified as a target gene of miR-21. Therefore, our study showed the protective effects of serum EVs on AMI, and provided a novel strategy for AMI therapy.

MicroRNA-21/PDCD4 Proapoptotic Signaling From Circulating CD34+ Cells to Vascular Endothelial Cells: A Potential Contributor to Adverse Cardiovascular Outcomes in Patients With Critical Limb Ischemia

“…miR-21, one of the most highly expressed miRs in mammalian cells, is modulated in cardiovascular disease (19)(20)(21)(22)(23). However, little is known regarding the expression of miR-21 in hematopoietic progenitor cells.…”

Extracellular Endothelial Cell-Derived Vesicles: Emerging Role in Cardiac and Vascular Remodeling in Heart Failure

“…For instance, mi-RNA-26a,−103, -and 107 have been shown to predominantly be regulators for insulin receptor function and free fatty acid metabolism (53,(110)(111)(112)(113)(114)(115)(116). Additionally, recent pre-clinical studies have revealed that mi-RNA-378 and mi-RNA-451 may play a crucial role in energy metabolism control through interacting with carnitine O-acetyltransferase, the peroxisome proliferator-activated receptor γ coactivator 1β, and LKB1/AMPK-signaling (117)(118)(119).…”

“…Additionally, EVs accumulate in the ischemic myocardium and regulate local inflammatory responses and vascular function through Erk1/2 STAT, Akt/MAPK-NF-κB signaling pathway (69,112). Therefore, NLRP3 inflammasomes and endothelial cell-derived EVs act as cargo for a wide spectrum There is evidence showing that mi-RNA-21, after a delivery into cardiac myocytes and endothelial cells, have reduced apoptosis through decreases in Programmed Cell Death gene-4 expression, inhibition of the extracellular inhibitor of the sprout regulated kinase 1 (Spry1), and stimulation of the expression of VEGF (53,67,113). In animal models, the protective effect of microRNA-21 against ischemia-induced myocardial damage was confirmed by diminished cell apoptosis around the infarcted areas after treatment with antibody vs. miRNA-21 (114).…”

“…Interestingly, there are some mi-RNAs (-146a,−155) that were associated with various metabolic comorbidities (type 2 diabetes mellitus, abdominal obesity, resistance to insulin) among patients with HF and adverse cardiac remodeling (70,108), but the role of endothelial cell-derived EVs in transportation of these molecules still needs to be confirmed further. In contrast, micro-RNA-126 being a component of endothelial cell-derived EVs mediates protein kinase G activity, VCAM-1 expression on the surface of endothelial cells, and increases monocyte recruitment and differentiation (53,90,(109)(110)(111)(112)(113)(114)(115)(116)(117)(118)(119). Several specific mi-RNAs (-92a,−126, and−133) were determined as regulators of microvascular coronary endothelial function and blood coagulation (120,121), and mi-RNA-138 and−155 were negatively associated with NO production and cell-cell communication, respectively (122,123).…”

Human peripheral blood‑derived exosomes for microRNA delivery

“…To date, a number of studies have suggested that extracellular vesicles (EVs) from in vitro cultured-cells or serum possess cardioprotective effects due to miRNAs, already present in the EVs (34,35); however, these studies have focused on the function of EVs as protective vesicles as opposed to drug carriers. Notably, the present study, to the best of our knowledge, provides the first compelling evidence that human peripheral blood-derived exosomes may be successfully used as a delivery vehicle for miRNA.…”