Exosomal CircHIPK3 Released from Hypoxia-Induced Cardiomyocytes Regulates Cardiac Angiogenesis after Myocardial Infarction

Abstract

Exosomes play critical roles in mediating cell-to-cell communication by delivering noncoding RNAs (including miRNAs, lncRNAs, and circRNAs). Our previous study found that cardiomyocytes (CMs) subjected to hypoxia released circHIPK3-rich exosomes to regulate oxidative stress damage in cardiac endothelial cells. However, the role of exosomes in regulating angiogenesis after myocardial infarction (MI) remains unknown. The aim of this study was to establish the effects of exosomes derived from hypoxia-induced CMs on the migration and angiogenic tube formation of cardiac endothelial cells. Here, we reported that hypoxic exosomes (HPC-exos) can effectively reduce the infarct area and promote angiogenesis in the border surrounding the infarcted area. HPC-exos can also promote cardiac endothelial cell migration, proliferation, and tube formation in vitro. However, these effects were weakened after silencing circHIPK3 in hypoxia-induced CMs. We further verified that silencing and overexpressing circHIPK3 changed cardiac endothelial cell proliferation, migration, and tube formation in vitro by regulating the miR-29a expression. In addition, exosomal circHIPK3 derived from hypoxia-induced CMs first led to increased VEGFA expression by inhibiting miR-29a activity and then promoted accelerated cell cycle progression and proliferation in cardiac endothelial cells. Overexpression of miR-29a mimicked the effect of silencing circHIPK3 on cardiac endothelial cell activity in vitro. Thus, our study provides a novel mechanism by which exosomal circRNAs are involved in the communication between CMs and cardiac endothelial cells.

CircHIPK3 regulates the autophagy and apoptosis of hypoxia/reoxygenation-stimulated cardiomyocytes via the miR-20b-5p/ATG7 axis

“…Neonatal mouse ventricular cardiomyocytes were isolated from 1- to 3-day-old C57BL/6J mice as previously described 12 , 13 . Briefly, neonatal mice were euthanized after performing heparinization for 5–10 min.…”

“…For instance, autophagy-related circRNA ACR can attenuate myocardial I/R injury by regulating the Pink1/FAM65B pathway to inhibit autophagy 11 . Our previous research found that cardiomyocytes undergoing hypoxia preconditioning could release circHIPK3-rich exosomes, thereby regulating the proliferation and apoptosis of endothelial cells underneath oxidative stress damage 12 , 13 . Furthermore, recent studies have shown that circHIPK3 regulates autophagy in STK11 mutant lung cancer through miR-124-3p/STAT3/PRKAA/AMPKα signaling 14 .…”

Exosomes in atherosclerosis: performers, bystanders, biomarkers, and therapeutic targets

“…For instance, plasma exosomal hsa_circ_0005540 was found to be a promising diagnostic biomarker of coronary artery disease 58 . Further, exosomal circHIPK3 was found to participate in the regulation of cardiac vascular injury and angiogenesis after myocardial infarction, suggesting a new mechanism of cellular communication in cardiovascular diseases mediated by exosomal circRNA 34 , 59 . In addition, increased circ_0003204 in extracellular vesicles was found to stimulate ectopic endothelial inactivation in cerebrovascular atherogenesis 60 .…”

Emerging Clues of Regulatory Roles of Circular RNAs through Modulating Oxidative Stress: Focus on Neurological and Vascular Diseases

“…circHIPK3 overexpression significantly decreases apoptosis and protects CMVECs against H 2 O 2 -5 Oxidative Medicine and Cellular Longevity [78]. It is also reported that cardiac endothelial cells can internalize exosomes containing circHIPK3 and increase circHIPK3 levels causing inhibition of miR-29a activity, increasing VEGFA expression, and regulating angiogenesis [79]. In high glucose-(HG-) induced HUVECs, the expression of circBPTF (bromodomain PHD finger transcription factor) is upregulated.…”