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Murine Myocardial Infarction Model using Permanent Ligation of Left Anterior Descending Coronary Artery
Published on: August 16, 2019
Neutrophil Elastase Deficiency Ameliorates Myocardial Injury Post Myocardial Infarction in Mice
Yukino Ogura1, Kazuko Tajiri1, Nobuyuki Murakoshi1
1Department of Cardiology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
Insights
Neutrophil elastase (NE) exacerbates myocardial infarction (MI) injury by increasing inflammation and suppressing survival signaling. Inhibiting NE improves cardiac function and survival post-MI, suggesting NE is a potential therapeutic target.
Area of Science:
- Cardiology
- Immunology
- Molecular Biology
Background:
- Neutrophils infiltrate the heart post-myocardial infarction (MI), releasing neutrophil elastase (NE).
- NE activity is elevated in MI patients, but its specific role in MI pathogenesis is unclear.
- This study investigates the role of NE in mouse models of MI.
Purpose of the Study:
- To elucidate the role of neutrophil elastase (NE) in the pathogenesis of myocardial infarction (MI).
- To evaluate the therapeutic potential of NE inhibition in MI treatment.
Main Methods:
- Investigated NE expression dynamics in infarcted mouse hearts.
- Assessed cardiac function, survival rates, and fibrosis in NE-deficient and wild-type mice post-MI.
- Utilized flow cytometry to analyze immune cell infiltration and Western blotting for signaling pathway analysis.
- Administered sivelestat, an NE inhibitor, to evaluate its therapeutic effects.
Main Results:
- NE expression peaked on day 1 post-MI.
- NE deficiency and sivelestat treatment improved survival and cardiac function post-MI.
- Reduced infiltration of neutrophils and inflammatory macrophages observed in NE-deficient mice.
- NE deficiency led to decreased apoptosis and upregulated insulin/Akt signaling in the heart.
- NE appears to enhance myocardial injury by promoting inflammation and inhibiting Akt signaling.
Conclusions:
- Neutrophil elastase (NE) plays a detrimental role in myocardial infarction (MI) pathogenesis.
- Inhibition of NE improves cardiac outcomes post-MI by reducing inflammation and enhancing survival pathways.
- Targeting NE represents a promising therapeutic strategy for managing MI.
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.
