Myocardial ischemia-reperfusion injury is probably due to the excessive production of mitochondrial ROS caused by the activation of 5-HT degradation system mediated by PAF receptor

Jiaqi Jin; Fan Xu; Yuxin Zhang; Jing Guan; Jihua Fu

doi:10.1016/j.molimm.2023.01.004

Myocardial ischemia-reperfusion injury is probably due to the excessive production of mitochondrial ROS caused by the activation of 5-HT degradation system mediated by PAF receptor

Mol Immunol. 2023 Mar:155:27-43. doi: 10.1016/j.molimm.2023.01.004. Epub 2023 Jan 20.

Authors

Jiaqi Jin¹, Fan Xu¹, Yuxin Zhang¹, Jing Guan¹, Jihua Fu²

Affiliations

¹ Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
² Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: jihua_fu@cpu.edu.cn.

PMID: 36682136
DOI: 10.1016/j.molimm.2023.01.004

Abstract

Aim: Previously, we revealed a crucial role of 5-HT degradation system (5DS), consisting of 5-HT2A receptor (5-HT2AR), 5-HT synthases and monoamine oxidase A (MAO-A), in ischemia-reperfusion (IR)-caused organ injury. Whereas, platelet activating factor receptor (PAFR) also mediates myocardial ischemia-reperfusion injury (MIRI). Here, we try to clarify the relationship between 5DS and PAFR in mediating MIRI.

Methods: H9c2 cell injury and rat MIRI were caused by hypoxia/reoxygenation (H/R) or PAF, and by ligating the left anterior descending coronary artery then untying, respectively. 5-HT_2AR and PAFR antagonists [sarpogrelate hydrochloride (SH) and BN52021], MAO-A, AKT, mTOR and 5-HT synthase inhibitors (clorgyline, perifosine, rapamycin and carbidopa), and gene-silencing PKCε were used in experiments RESULTS: The mitochondrial ROS production, respiratory chain damage, inflammation, apoptosis and myocardial infarction were significantly prevented by BN52021, SH and clorgyline in H/R and PAF-treated cells and in IR myocardium. BN52021 also significantly suppressed the upregulation of PAFR, 5-HT_2AR, 5-HT synthases and MAO-A expression (mRNA and protein), and Gα_q and PKCε (in plasmalemma) expression induced by H/R, PAF or IR; the effects of SH were similar to that of BN52021 except for no affecting the expression of PAFR and 5-HT_2AR. Gene-silencing PKCε suppressed H/R and PAF-induced upregulation of 5-HT synthases and MAO-A expression in cells; perifosine and rapamycin had not such effects; however, clorgyline suppressed H/R and PAF-induced phosphorylation of AKT and mTOR.

Conclusion: MIRI is probably due to PAFR-mediated 5-HT_2AR activation, which further activates PKCε-mediated 5-HT synthesis and degradation, leading to mitochondrial ROS production.

Keywords: 5-hydroxytryptaminedegradation system; Mitochondria; Myocardial ischemia-reperfusion injury; Platelet activating factorreceptor; Protein kinase Cε; Reactive oxygen species.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Clorgyline / pharmacology
Monoamine Oxidase / metabolism
Monoamine Oxidase / pharmacology
Myocardial Reperfusion Injury* / metabolism
Platelet Membrane Glycoproteins* / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Rats
Reactive Oxygen Species* / metabolism
Reactive Oxygen Species* / toxicity
Receptors, G-Protein-Coupled* / metabolism
Serotonin* / metabolism
Serotonin* / pharmacology
TOR Serine-Threonine Kinases / metabolism

Substances

Clorgyline
Monoamine Oxidase
perifosine
platelet activating factor receptor
Platelet Membrane Glycoproteins
Proto-Oncogene Proteins c-akt
Reactive Oxygen Species
Receptors, G-Protein-Coupled
Serotonin
TOR Serine-Threonine Kinases