Exosomes Released from CaSR‐Stimulated PMNs Reduce Ischaemia/Reperfusion Injury

Abstract

Ischemia-reperfusion (I/R) injury caused by acute myocardial infarction (AMI) can initiate a strong inflammatory response. Polymorphonuclear cells (PMNs) are the most important inflammatory cells. Our previous studies found that the calcium-sensing receptor (CaSR) regulates the proinflammatory effects of PMNs. However, the role and mechanism of CaSR-regulated PMNs in I/R injury remain uncertain. A rat AMI model was developed in this study and showed that the expression of CaSR on PMNs increased in AMI; however, the levels of Bcl-xl and SOD in myocardial tissue decreased, while Bax and MDA levels increased. Then, after coculture with CaSR-stimulated PMNs, the expression of Bcl-xl in cardiomyocytes significantly increased, Bax expression and the apoptotic rate decreased, and ROS production was significantly inhibited. At the same time, the cardiomyocyte damage caused by hypoxia-reoxygenation was reduced. Furthermore, we found that exosomes derived from PMNs could be taken up by cardiomyocytes. Additionally, the exosomes secreted by CaSR-stimulated PMNs had the same effect on cardiomyocytes as CaSR-stimulated PMNs, while the increased phosphorylation level of AKT in cardiomyocytes could be revered by AKT transduction pathway inhibitors. Subsequently, we identified the exosomes derived from CaSR-stimulated PMNs by second-generation sequencing technology, and increased expression of lncRNA ENSRNOT00000039868 was noted. The data show that this lncRNA can prevent the hypoxia-reoxygenation injury by upregulating the expression of PDGFD in cardiomyocytes. In vivo, exosomes from CaSR-stimulated PMNs played a significant role against AMI and reperfusion injury in myocardial tissue. Thus, we propose that exosomes derived from CaSR-stimulated PMNs can reduce I/R injury in AMI, and this effect may be related to the AKT signaling pathway.

New Developments in Exosomal lncRNAs in Cardiovascular Diseases

“…In vivo experiments showed that after intravenous injection of CaSR-PMN-exos via the tail vein in rats, the area of myocardial infarction and MDA secretion were significantly reduced, the SOD levels were increased, and cardiac function was improved. These results suggest that CaSR-PMN-exosomal lncRNA 39868 upregulates the protein PDGFD, regulates these effects through the AKT pathway, and reduces MIRI ( 55 ).…”

Full-length transcriptome analysis reveals the mechanism of acupuncture at PC6 improves cardiac function in myocardial ischemia model

“…To investigated the mechanism of acupuncture against MI injury from a more comprehensive perspective, we studied the transcriptome from the aspects of differential genes, alternative splicing, and new genes by full-length transcriptome. In previous studies on MI, Second-generation sequencing technology (SGS) has been widely used [11,23,40,48]. However, the shortread RNA-seq method of SGS is limited to identify and quantify complex transcript isoforms.…”

Extracellular lncRNAs secreted and absorbed by cardiomyocytes

“…Polymorphonuclear neutrophils (PMNs) are very important inflammatory cells. Recent study reported that exosomal lncRNA ENSRNOT00000039868 (lncRNA 39868) mediated the communications between PMNs and I/R CMs 52 . The calcium‐sensing receptor (CaSR) was found to be significantly upregulated in rat peripheral blood PMNs in acute MI and I/R CMs model in vitro 52 .…”

“…Recent study reported that exosomal lncRNA ENSRNOT00000039868 (lncRNA 39868) mediated the communications between PMNs and I/R CMs 52 . The calcium‐sensing receptor (CaSR) was found to be significantly upregulated in rat peripheral blood PMNs in acute MI and I/R CMs model in vitro 52 . CIN PMNs (CaSR activated) decreased Bax (proapoptotic protein) levels while increased Bcl‐xl levels.…”

“…Exosomes have been revealed to be released from cardiac cells within the heart and exosomal miRNAs have been demonstrated to be involved in the pathogenesis of cardiac hypertrophy, cardiomyopathy, atrial fibrillation (AF) 34–36 . Exosomal lncRNAs were also found to participate in the development of acute MI, cardiac angiogenesis, and ischemia‐reperfusion injury 37,38 . Among of these cells in heart, CMs nearly account for around 75% of the heart volume, which determine the levels of exosomes in heart to a large extent 39 .…”