Neutrophil Gelatinase-Associated Lipocalin2 Exaggerates Cardiomyocyte Hypoxia Injury by Inhibiting Integrin β3 Signaling

Gu, Yang; Geng, Jin; Xu, Zhuo; Chen, Yu; Zhang, Xiwen

doi:10.12659/msm.915108

Cited by 6 publications

(5 citation statements)

References 25 publications

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“…Neutrophils rely on Lcn2 to generate ROS while fighting bacteria 22 . However, this defense mechanism can become deleterious, damaging ischemic cardiomyocytes 23 , 24 . Serum LCN2, also known as neutrophil gelatinase-associated lipocalin (NGAL), increases in patients with MI and heart failure and predicts infarct mortality and adverse outcomes 25 .…”

Section: Resultsmentioning

confidence: 99%

Neutrophils incite and macrophages avert electrical storm after myocardial infarction

Grune

Lewis²,

Yamazoe³

et al. 2022

Nat Cardiovasc Res

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Sudden cardiac death, arising from abnormal electrical conduction, occurs frequently in patients with coronary heart disease. Myocardial ischemia simultaneously induces arrhythmia and massive myocardial leukocyte changes. In this study, we optimized a mouse model in which hypokalemia combined with myocardial infarction triggered spontaneous ventricular tachycardia in ambulatory mice, and we showed that major leukocyte subsets have opposing effects on cardiac conduction. Neutrophils increased ventricular tachycardia via lipocalin-2 in mice, whereas neutrophilia associated with ventricular tachycardia in patients. In contrast, macrophages protected against arrhythmia. Depleting recruited macrophages in Ccr2−/− mice or all macrophage subsets with Csf1 receptor inhibition increased both ventricular tachycardia and fibrillation. Higher arrhythmia burden and mortality in Cd36−/− and Mertk−/− mice, viewed together with reduced mitochondrial integrity and accelerated cardiomyocyte death in the absence of macrophages, indicated that receptor-mediated phagocytosis protects against lethal electrical storm. Thus, modulation of leukocyte function provides a potential therapeutic pathway for reducing the risk of sudden cardiac death.

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Section: Resultsmentioning

confidence: 99%

Neutrophils incite and macrophages avert electrical storm after myocardial infarction

Grune

Lewis²,

Yamazoe³

et al. 2022

Nat Cardiovasc Res

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“…Hypoxia exacerbates cardiomyocyte injury through Wnt3a-Sirt3 and cardiomyocyte apoptosis [28]. Inhibition of integrin ß3 signaling can deteriorate hypoxia injury of cardiomyocytes through inflammatory response, and apoptosis [29]. Resveratrol protected against hypoxia-induced neonatal rat cardiomyocytes injury through regulating Sirt1/p53-mediated apoptosis and NLRP3-mediated inflammation [30].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Induced Cardiomyocyte Apoptosis Exacerbates Cardiomyocyte Hypertrophy and Myocardial Injury through p38 MAPK Pathway in SD Rats

Li¹,

Pu²,

Xu³

et al. 2023

Preprint

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Right ventricular remodeling and its function are closely related to the symptom severity and survival of hypoxia pulmonary hypertension, but molecular mechanisms of cardiomyocyte hypertrophy and myocardial injury remain unclear. It evaluated the cardiac function (by right cardiac catheterization to measure right ventricular systolic pressure and mean pulmonary artery pressure), myocardial tissue morphology（Haematoxylin and Eosin）, myocardial hypertrophy (Wheat Germ Agglutinin Staining), then RNA sequencing was applied to explore the mechanism, which results were verified by western blot in final. Hypoxia developed pulmonary hypertension, right ventricular diastolic and systolic functions were enhanced in rats, such as the mean pulmonary artery pressure, systolic pressure of pulmonary artery, the max pressure of right ventricular, the mean right ventricular pressure, and the heart rate was significantly higher than that in control. We found that Hif-1 signaling pathway and p38-MAPK signaling pathway have been activated by hypoxia, and cardiomyocyte apoptosis also aggravated in the right ventricular, which might be one cause of cardiomyocyte hypertrophy and myocardial injury, and targeted intervention might be one potential prevention for cardiomyocyte hypertrophy and myocardial injury induced by hypoxia.

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“…In this study, we found that NE deletion increased P-Akt levels in the heart post-MI ( Figure 4 ). Akt has been reported to reduce inflammatory responses in various cells, including cardiomyocytes [ 21 , 22 , 23 ]. Thus, a decrease in Akt signaling induced by NE may also contribute to excessive inflammation post-MI.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil Elastase Deficiency Ameliorates Myocardial Injury Post Myocardial Infarction in Mice

Ogura

Tajiri

Murakoshi

et al. 2021

IJMS

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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.

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Neutrophil Gelatinase-Associated Lipocalin2 Exaggerates Cardiomyocyte Hypoxia Injury by Inhibiting Integrin β3 Signaling

Cited by 6 publications

References 25 publications

Neutrophils incite and macrophages avert electrical storm after myocardial infarction

Neutrophils incite and macrophages avert electrical storm after myocardial infarction

Hypoxia-Induced Cardiomyocyte Apoptosis Exacerbates Cardiomyocyte Hypertrophy and Myocardial Injury through p38 MAPK Pathway in SD Rats

Neutrophil Elastase Deficiency Ameliorates Myocardial Injury Post Myocardial Infarction in Mice

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