Rev-erb agonist improves adverse cardiac remodeling and survival in myocardial infarction through an anti-inflammatory mechanism.

Endin Nokik Stujanna,Yukino Ogura,Taizo Kimura,Saori Yonebayashi,Kazutaka Aonuma,Akira Sato,Nobuyuki Murakoshi,Rujie Qin,Kazuko Tajiri,Dongzhu Xu,Duo Feng,Fumi Yamagami,Akihiko Nogami,Guo-Chang Fan

doi:10.1371/journal.pone.0189330

Abstract

Rev-erb α, known as nuclear receptor 1D1 (NR1D1), regulates circadian rhythm, modulates glucose and lipid metabolism, and inflammatory response. However, little is known about the effect of Rev-erb agonist on the progression of myocardial infarction (MI) and heart failure. To investigate it, wild-type male mice underwent sham-operation or permanent ligation of the left anterior descending coronary artery to create MI model. Rev-erb agonist SR9009 (100 mg/kg/day) or vehicle was intraperitoneally administered. Echocardiography was performed to evaluate cardiac function 1 week after surgery. The gene and protein expression levels in the left ventricles (LVs) were determined with real-time PCR, western blotting, and immunofluorescence. Moreover, immune cell infiltration into the LVs was analyzed by flow cytometry. Survival rate and reduced LV function were significantly improved by the treatment with SR9009 after MI. The expression level and plasma concentration of brain natriuretic peptide were significantly lower in MI mice treated with SR9009 (MI+SR) than in MI mice treated with vehicle (MI+V). Moreover, the mRNA expression levels of inflammatory-related molecules such as Il6, Mcp1, Ly6g, Cd11b, matrix metallopeptidase (Mmp)9, and the protein expression levels of phosphorylated NF-κB p65, phosphorylated ERK, and phosphorylated p38 were also significantly lower in MI+SR than in MI+V. Immunofluorescence intensity for MMP-9 was enhanced in the LVs, but was less so in MI+SR than in MI+V. Furthermore, infiltrations of neutrophils and proinflammatory macrophages in the LVs were dramatically increased in MI+V and were significantly suppressed in MI+SR. Rev-erb agonist SR9009 treatment inhibited post-MI mortality and improved cardiac function through modulating inflammation and remodeling process.

Highlights

As a leading cause of death worldwide, myocardial infarction (MI) remains one of the most important clinical entities
Plasma BNP concentration was significantly higher in mice treated with vehicle (MI+V) than in Sham +V, and it was significantly lower in mice treated with SR9009 (MI+SR) than in MI+V (Fig 5G). These results suggested that elevated BNP, infiltration of neutrophils and monocytes/macrophages, and productions of inflammatory cytokines and extracellular matrix were reduced by the treatment with SR9009 during the acute phase of MI
We showed for the first time, to our knowledge, that Rev-erb agonist SR9009 improved left ventricles (LVs) function and survival after MI

Summary

Introduction

As a leading cause of death worldwide, myocardial infarction (MI) remains one of the most important clinical entities. After the onset of MI, cardiac tissue undergoes sequential molecular and cellular responses called remodeling [1]. Neutrophils and monocytes are recruited around the necrotic tissue, and they release inflammatory cytokines and matrix metalloproteinases (MMPs) [2]. These processes play important roles in the degradation of necrotic debris and subsequent scar formation, excess inflammatory response and MMP overproduction are likely to induce adverse cardiac remodeling, leading to cardiac dysfunction and rupture [3,4]. Despite the significant progress made on therapeutic strategies for MI in last few decades, mortality and morbidity remain high, and adverse cardiac remodeling after MI remains a critical issue to be solved. Continuous improvement in medications for the disease is still a major concern in global medical research

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