Neutrophil Elastase Deficiency Ameliorates Myocardial Injury Post Myocardial Infarction in Mice.

Yukino Ogura,Siqi Li,Duo Feng,Yuta Okabe,Dongzhu Xu,Kazuko Tajiri,Kazutaka Aonuma,Masaki Ieda,Zoughu Song,Yuzuno Shimoda,Saori Yonebayashi,Nobuyuki Murakoshi,Haruka Mori,Zixun Yuan

doi:10.3390/ijms22020722

Yukino Ogura, Siqi Li + Show 12 more

Open Access

https://doi.org/10.3390/ijms22020722

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Abstract

Neutrophils are recruited into the heart at an early stage following a myocardial infarction (MI). These secrete several proteases, one of them being neutrophil elastase (NE), which promotes inflammatory responses in several disease models. It has been shown that there is an increase in NE activity in patients with MI; however, the role of NE in MI remains unclear. Therefore, the present study aimed to investigate the role of NE in the pathogenesis of MI in mice. NE expression peaked on day 1 in the infarcted hearts. In addition, NE deficiency improved survival and cardiac function post-MI, limiting fibrosis in the noninfarcted myocardium. Sivelestat, an NE inhibitor, also improved survival and cardiac function post-MI. Flow cytometric analysis showed that the numbers of heart-infiltrating neutrophils and inflammatory macrophages (CD11b+F4/80+CD206low cells) were significantly lower in NE-deficient mice than in wild-type (WT) mice. At the border zone between intact and necrotic areas, the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells was lower in NE-deficient mice than in WT mice. Western blot analyses revealed that the expression levels of insulin receptor substrate 1 and phosphorylation of Akt were significantly upregulated in NE-knockout mouse hearts, indicating that NE deficiency might improve cardiac survival by upregulating insulin/Akt signaling post-MI. Thus, NE may enhance myocardial injury by inducing an excessive inflammatory response and suppressing Akt signaling in cardiomyocytes. Inhibition of NE might serve as a novel therapeutic target in the treatment of MI.

Highlights

Ischemic cardiovascular diseases, acute myocardial infarction (MI), are one of the leading causes of mortality worldwide [1]
Echocardiographic examination and cardiac catheterization experiments revealed that Elane−/− mice had improved cardiac function (preserved fractional shortening (FS) and increased +dP/dt), as compared to WT mice (Figure 2D,E). These results suggest that Neutrophil elastase (NE) increases fibrosis size and exacerbates cardiac function post-MI
The phosphorylation levels of Akt were lower in WT MI hearts than in Elane−/− MI hearts (Figure 4A,B). These results suggest that NE deficiency might improve cardiomyocyte survival by increasing insulin/Akt signaling post-MI

Summary

Introduction

Acute myocardial infarction (MI), are one of the leading causes of mortality worldwide [1]. In the past few decades, with the advancement and innovation of pharmacological and interventional therapies, the acute mortality rate of MI has reduced remarkably [2]. Following an MI, an inflammatory response is directed to the site of injury, resulting in structural and biochemical changes that can lead to cardiac remodeling [4]. Neutrophils are one of the major leukocytes involved in the inflammatory response to MI. During the first hours post-MI, neutrophils massively infiltrate into the infarct area [5]. NE damages directly invading pathogens and fine-tunes the host inflammatory response for better pathogen eradication and its associated inflammation [7]

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