ω-Alkynyl arachidonic acid induces anti-inflammatory M2 polarization of macrophages in acute myocardial infarction via regulating the cross-talk between PKM2, iNOS and HIF-1α

Dr Rong, Jianhui   (Principal Investigator (PI))

Professor Li Xuechen   (Co-Investigator)

Dr Xia Zhengyuan   (Co-Investigator)

Professor Feng Yibin   (Co-Investigator)

36

2017-01-01

1088950

ω-Alkynyl arachidonic acid induces anti-inflammatory M2 polarization of macrophages in acute myocardial infarction via regulating the cross-talk between PKM2, iNOS and HIF-1α

acute myocardial infarction, arachidonic acid metabolism, macrophage polarization, molecular mechanism, pyruvate kinase M2

Traditional Chinese Medicine (basic),Pharmacology/Toxicology

Biology and Medicine (M)

17146216

General Research Fund (GRF)

2016

Completed

1 The first objective is to identify the impact of ω-alkynyl-AA-PKM2 conjugation on macrophage M2 polarization. In pilot experiments, we discovered that ω-alkynyl-AA formed covalent conjugate with glycolytic enzyme PKM2. PKM2 not only govern energy metabolism via glycolysis but also regulate the transcriptional activity of HIF-1α. We postulate that ω-alkynyl-AA may regulate macrophage polarization via suicide inhibition of PKM2 activities. We will discover which and how ω-alkynyl-AA metabolites form covalent conjugate with PKM2. We will also determine whether the conjugation of ω-alkynyl-AA with PKM2 alters the effects of PKM2 on macrophage polarization. 2 The second objective is to clarify whether ω-alkynyl-AA promotes macrophage polarization via regulating the cross-talk between PKM2, iNOS and HIF-1α. Other scientists have demonstrated that PKM2 and iNOS could individually regulate the transcriptional activity of HIF-1α. Our results indicated that ω-alkynyl-AA not only formed covalent conjugate with PKM2 but also down-regulated PKM2, iNOS and HIF-1α expression.Thus, we hypothesize that ω-alkynyl-AA may promote macrophage polarization via regulating the cross-talk between PKM2, iNOS and HIF-1α. We will address three important questions: 1) Does the formation of ω-alkynyl-AA-PKM2 conjugate cause down-regulation of PKM2, iNOS and HIF-1α? 2) Does PKM2 suppression down-regulate HIF-1α and iNOS expression or iNOS suppression lead to the decrease in PKM2 and HIF-1α expression? 3) Does ω-alkynyl-AA promote macrophage polarization in PKM2-, iNOS- or HIF-1α-dependent manner? 3 The third objective is to determine the in vivo cardioprotective efficacy of ω-alkynyl-AA in mice. The abnormalities of arachidonic acid metabolism may cause myocardial infarction. However, we found that ω-alkynyl-AA reduced infarct size and cardiac damage in mouse model. Thus, we hypothesize that ω-alkynyl-AA attenuates cardiac injury via promoting anti-inflammatory M2 polarization of macrophage. After inducing myocardial infarction in mice by coronary ligation, we will determine the efficacy of ω-alkynyl-AA to reduce infarct size, myocardial injury and redox status. We will also investigate the effects of ω-alkynyl-AA on the phenotypic kinetics of resident cardiac macrophages and myocardial fibrosis in the infarcted hearts.