Neutrophil Elastase Deficiency Ameliorates Myocardial Injury Post Myocardial Infarction in Mice

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.

The Emerging Role of Neutrophils in the Pathogenesis of Thrombosis in COVID-19

“…The role of NE in patients with ARDS, including COVID-19, and sepsis have been reported in different studies [104][105][106][107]. Moreover, in an experimental mice model, Ogura et al reported that NE deficiency improves myocardial injury in post-myocardial infarction [108]. Based on previous reports, NE inhibition could potentially have positive effects on COVID-19 [109].…”

Neutrophil degranulation and myocardial infarction

“…The protective effect was associated with reducing neutrophil activation and vascular leakage [ 61 ]. NE reached its peak on day1 in the infarcted mouse hearts [ 62 ]. NE deficiency decreased mouse mortality, increased cardiac function, and reduced fibrosis in the non-infarcted myocardium [ 62 ].…”

Hindrance of the Proteolytic Activity of Neutrophil-Derived Serine Proteases by Serine Protease Inhibitors as a Management of Cardiovascular Diseases and Chronic Inflammation

“…Pulmonary arterial hypertension (PAH) is characterized by higher catalytic activity of NE hydrolyzing extracellular matrix components (elastin, laminin, collagen, and fibronectin) which in turn release epidermal growth factor (EGF) and fibroblast growth factor (FGF), leading to adverse vascular remodeling ( Zhu et al, 1994 ; Taylor et al, 2018 ). NE-deficient mice possess an improved cardiac survival rate after myocardial infarction, indicating reduced inflammation and suppression of the Akt signaling pathway ( Ogura et al, 2021 ). Of interest is the fact that administration of Sivelestat, a NE inhibitor, restored cardiac functioning post myocardial infarction in mice ( Ogura et al, 2021 ).…”

“…NE-deficient mice possess an improved cardiac survival rate after myocardial infarction, indicating reduced inflammation and suppression of the Akt signaling pathway ( Ogura et al, 2021 ). Of interest is the fact that administration of Sivelestat, a NE inhibitor, restored cardiac functioning post myocardial infarction in mice ( Ogura et al, 2021 ). Moreover, elevated NE levels in plasma correlate with the severity of numerous cardiovascular diseases including coronary artery disease (CAD), ischemic heart disease, and angina pectoris ( Mehta et al, 1989 ; Bell et al, 1990 ; Smith et al, 2000 ).…”