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Neutrophil Elastase Deficiency Ameliorates Myocardial Injury Post Myocardial Infarction in Mice
- Source :
- International Journal of Molecular Sciences, Volume 22, Issue 2, International Journal of Molecular Sciences, Vol 22, Iss 722, p 722 (2021)
- Publication Year :
- 2021
- Publisher :
- MDPI, 2021.
-
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<br />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.
- Subjects :
- 0301 basic medicine
Neutrophils
Biopsy
Insulins
030204 cardiovascular system & hematology
lcsh:Chemistry
Mice
chemistry.chemical_compound
0302 clinical medicine
Fibrosis
Myocytes, Cardiac
lcsh:QH301-705.5
Spectroscopy
remodeling
Mice, Knockout
TUNEL assay
Ventricular Remodeling
biology
Sivelestat
apoptosis
neutrophil
General Medicine
Prognosis
Computer Science Applications
myocardial infarction
Neutrophil elastase
Heart Function Tests
neutrophil elastase
Signal Transduction
medicine.medical_specialty
macromolecular substances
Article
Catalysis
Inorganic Chemistry
03 medical and health sciences
Downregulation and upregulation
Internal medicine
medicine
Animals
Physical and Theoretical Chemistry
Molecular Biology
Protein kinase B
sivelestat
business.industry
Myocardium
Organic Chemistry
medicine.disease
IRS1
Disease Models, Animal
030104 developmental biology
Endocrinology
lcsh:Biology (General)
lcsh:QD1-999
chemistry
Terminal deoxynucleotidyl transferase
biology.protein
Leukocyte Elastase
business
Proto-Oncogene Proteins c-akt
Biomarkers
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Volume :
- 22
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....cfd3eb2c0f6796e2d7399e03bfdbb8e1