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Exosomes Released from CaSR-Stimulated PMNs Reduce Ischaemia/Reperfusion Injury
Tai-Yu Zhai1, Bao-Hong Cui1, Yang Zhou1
1Department of Clinical Laboratory, Harbin Medical University Cancer Hospital, Harbin 150086, China.
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.
Insights
Calcium-sensing receptor (CaSR) activation on polymorphonuclear cells (PMNs) reduces ischemia-reperfusion (I/R) injury in acute myocardial infarction (AMI). Exosomes from these activated PMNs protect cardiomyocytes via the AKT pathway and lncRNA ENSRNOT00000039868.
Area of Science:
- Cardiovascular Biology
- Inflammation Research
- Cellular Signaling
Background:
- Ischemia-reperfusion (I/R) injury following acute myocardial infarction (AMI) triggers significant inflammation, primarily mediated by polymorphonuclear cells (PMNs).
- The calcium-sensing receptor (CaSR) is known to modulate PMN pro-inflammatory activities, but its specific role in I/R injury remains unclear.
- Understanding CaSR-regulated PMN mechanisms is crucial for developing novel therapeutic strategies against myocardial I/R injury.
Purpose of the Study:
- To investigate the role and mechanism of CaSR-regulated PMNs in a rat model of AMI-induced I/R injury.
- To elucidate the protective effects of PMN-derived exosomes on cardiomyocytes during hypoxia-reoxygenation.
- To identify specific molecular mediators, including long non-coding RNAs (lncRNAs), involved in the protective signaling.
Main Methods:
- Establishment of a rat AMI model to assess myocardial tissue and PMN changes.
- In vitro co-culture experiments of cardiomyocytes with CaSR-stimulated PMNs and their derived exosomes.
- Analysis of cell apoptosis, reactive oxygen species (ROS) production, and protein expression (Bcl-xl, Bax, AKT phosphorylation).
- Second-generation sequencing to identify exosomal lncRNAs and subsequent functional validation.
Main Results:
- CaSR expression on PMNs increased in AMI rats, correlating with altered myocardial tissue markers (decreased Bcl-xl/SOD, increased Bax/MDA).
- CaSR-stimulated PMNs and their exosomes significantly reduced cardiomyocyte apoptosis, ROS production, and damage from hypoxia-reoxygenation.
- Exosomes from CaSR-stimulated PMNs contain increased lncRNA ENSRNOT00000039868, which protects cardiomyocytes by upregulating PDGFD.
- PMN exosome-mediated protection involves the AKT signaling pathway, as evidenced by reversed AKT phosphorylation with pathway inhibitors.
Conclusions:
- Exosomes derived from CaSR-stimulated PMNs exert protective effects against myocardial I/R injury in AMI.
- The lncRNA ENSRNOT00000039868 within these exosomes plays a key role in cardiomyocyte protection.
- The AKT signaling pathway is implicated in the mechanism by which these exosomes mediate their cardioprotective effects.
