Myeloid peroxisome proliferator-activated receptor gamma deficiency aggravates myocardial infarction in mice. (July 2018)

• Record Type: Journal Article
• Authors: Shen, Zhu-Xia; Yang, Qing-Zhen; Li, Chao; Du, Lin-Juan; Sun, Xue-Nan; Liu, Yan; Sun, Jian-Yong; Gu, Hui-Hui; Sun, Yu-Min; Wang, Jun; Duan, Sheng-Zhong
• Is Part Of: Atherosclerosis. Volume 274(2018)
• Page Start: 199
• Page End: 205
• Publication Date: 2018-07
• Subjects: Ppar gamma -- Myocardial infarction -- Cardiac function -- NADPH oxidase -- Macrophage -- Inflammation; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2018.05.005
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: Agonists of peroxisome proliferator-activated receptor gamma (Pparγ) have been demonstrated to reduce the risk of myocardial infarction (MI) in clinical trials and animal experiments. However, the cellular and molecular mechanisms are not completely understood. We aimed to reveal the functions of myeloid Pparγ in MI and explore the potential mechanisms in this study. Methods: Myeloid Pparγ knockout ( MPGKO ) mice (n = 12) and control mice (n = 8) underwent coronary artery ligation to induce MI. Another cohort of MPGKO mice and control mice underwent coronary artery ligation and were then treated with IgG or neutralizing antibodies against interleukin (IL)-1β. Infarct size was determined by TTC staining and cardiac function was measured using echocardiography. Conditioned media from GW9662- or vehicle-treated macrophages were used to treat H9C2 cardiomyocyte cell line. Gene expression was analyzed using quantitative PCR. Reactive oxygen species were measured using flow cytometry. Results: Myeloid Pparγ deficiency significantly increased myocardial infarct size. Cardiac hypertrophy was also exacerbated in MPGKO mice, with upregulation of β-myosin heavy chain (Mhc) and brain natriuretic peptide (Bnp) and downregulation of α-Mhc in the non-infarcted zone. Conditioned media from GW9662-treated macrophages increased expression of β-Mhc and Bnp in H9C2 cells. Echocardiographic measurements showed that MPGKO mice had worsen cardiac dysfunction after MI. Myeloid Pparγ deficiency increased gene expression of NADPH oxidase subunits (Nox2 and Nox4) in the non-infarcted zone after MI. Conditioned media from GW9662-treated macrophages increased reactive oxygen species in H9C2 cells. Expression of inflammatory genes such as IL-1β and IL-6 was upregulated in the non-infarcted zone of MPGKO mice after MI. With the injection of neutralizing antibodies against IL-1β, control mice and MPGKO mice had comparable cardiac function and expression of inflammatory genes after MI. Conclusions: Myeloid Pparγ deficiency exacerbates MI, likely through increased oxidative stress and cardiac inflammation. Graphical abstract: Highlights: Myeloid PPARγ deficiency exacerbated myocardial infarct size, cardiac hypertrophy, and cardiac dysfunction post myocardial infarction in mice. Myeloid PPARγ deficiency exacerbated myocardial infarction likely through oxidative stress and cardiac inflammation. The results suggest that myeloid PPARγ is a potential therapeutic target for myocardial infarction.