scholarly journals Traditional Chinese Medicine Formulation Huangqi Jianzhong Tang Improves Cardiac Function after Myocardial Infarction in Rats

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Ya-Ru Bao ◽  
Wen-Yi Jiang ◽  
Jia-Yu Yu ◽  
Jing-Wei Chen ◽  
Guo-Xing Zhang
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Infarct Size ◽  
Heart Function ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Tunel Staining ◽  
High Dose ◽  
Therapeutic Effects ◽  
Myocardial Infarct Size ◽  
Radix Paeoniae Alba

Huangqi Jianzhong Tang (HQJZT) is a traditional Chinese herbal formula consisting of seven different herbs: Radix Astragali, Radix Paeoniae Alba, Ramulus Cinnamomi, Fructus Jujubae, Glycyrrhizae Radix Et Rhizoma Praeparata Cum Melle, Rhizoma Zingiberis Recens, and Saccharum Granorum. The present study aims to evaluate the possible effects of HQJZT on cardiac function in acute myocardial infarction (AMI) and related mechanism. AMI model was established by ligation of the left anterior descending coronary artery followed by one-week HQJZT treatment. Survival rate was calculated. Rat heart function was assessed by heart performance analysis system. 5-Triphenyltetrazolium chloride (TTC) staining was used to observe myocardial infarct size. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining and western blot were applied to evaluate tissue apoptotic level. Treatment with high dose of HQJZT improved cardiac function, reduced infarct size, number of apoptotic cells and expression of apoptotic proteins, Bax (a proapoptotic protein), and increased expression of antiapoptotic protein, Bcl2. However, enalapril (an angiotensin-converting enzyme inhibitor) treatment did not show marked improvement of these parameters. Our present data suggest that HQJZT has potential therapeutic effects to improve cardiac function by regulation of apoptotic signaling pathway.

scholarly journals Protective Mechanism of Trimetazidine in Myocardial Cells in Myocardial Infarction Rats through ERK Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Zhenjun Wu ◽  
Lihua Yu ◽  
Xinyue Li ◽  
Xuewen Li
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Infarct Size ◽  
Signaling Pathway ◽  
Dose Group ◽  
Myocardial Infarct ◽  
Erk Signaling ◽  
High Dose ◽  
Myocardial Infarct Size ◽  
Rat Cardiomyocytes

Objective. To study the protective effect of trimetazidine on myocardial cells in rats with myocardial infarction and explore its effect on ERK signaling pathway. Methods. 40 SD rats were randomly divided into the sham operation group, model group, low-dose group, and high-dose group (intra-abdominal injection of trimetazidine 5 mg/kg and 10 mg/kg, respectively), construction of rat myocardial infarction model by coronary artery left anterior descending artery ligation. 7 days after surgery, the survival rate and cardiac function of each group of rats were recorded. The myocardial infarct size was detected by TTC staining. The apoptosis level of rat cardiomyocytes was detected by TUNEL staining. The content of ROS in rat cardiomyocytes was detected by DCFH-DA. Western-blot was used to detection of Caspase-3, Bcl-2/Bax, and ERK signaling pathway-related proteins in myocardial tissue. Results. Compared with the model group, the survival rate of the rats in the low-dose group and the high-dose group was significantly increased ( P < 0.01 ), the cardiac function was significantly improved ( P < 0.01 ), the myocardial infarct size was significantly decreased ( P < 0.01 ), the level of apoptosis was significantly decreased ( P < 0.01 ), the content of ROS in cardiomyocytes was significantly decreased ( P < 0.01 ), the protein expression of Caspase-3 and NF-κB in cardiomyocytes was significantly decreased ( P < 0.01 ), and the expression of Bcl-2/Bax and p-ERK were significantly increased ( P < 0.01 ). Conclusion. Trimetazidine can activate ERK signaling pathway in cardiomyocytes of rats with myocardial infarction, increase the expression of p-ERK, decrease the content of ROS in cardiomyocytes, decrease the expression of apoptotic proteins, reduce myocardial infarct size, improve cardiac function, and increase myocardial function.

Cardioprotection with esmolol-based cardioplegia for non-infarcted and infarcted rat hearts

2021 ◽  
Author(s):  
Alexander B Veitinger ◽  
Audrey Komguem ◽  
Lena Assling-Simon ◽  
Martina Heep ◽  
Julia Schipke ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Lactate Production ◽  
Left Ventricular ◽  
Myocardial Infarct Size ◽  
Cardioplegic Arrest ◽  
Blood Cardioplegia ◽  
Rat Hearts

Abstract OBJECTIVES Esmolol-based cardioplegic arrest offers better cardioprotection than crystalloid cardioplegia but has been compared experimentally with blood cardioplegia only once. We investigated the influence of esmolol crystalloid cardioplegia (ECCP), esmolol blood cardioplegia (EBCP) and Calafiore blood cardioplegia (Cala) on cardiac function, metabolism and infarct size in non-infarcted and infarcted isolated rat hearts. METHODS Two studies were performed: (i) the hearts were subjected to a 90-min cardioplegic arrest with ECCP, EBCP or Cala and (ii) a regional myocardial infarction was created 30 min before a 90-min cardioplegic arrest. Left ventricular peak developed pressure (LVpdP), velocity of contractility (dLVP/dtmax), velocity of relaxation over time (dLVP/dtmin), heart rate and coronary flow were recorded. In addition, the metabolic parameters were analysed. The infarct size was determined by planimetry, and the myocardial damage was determined by electron microscopy. RESULTS In non-infarcted hearts, cardiac function was better preserved with ECCP than with EBCP or Cala relative to baseline values (LVpdP: 100 ± 28% vs 86 ± 11% vs 57 ± 7%; P = 0.002). Infarcted hearts showed similar haemodynamic recovery for ECCP, EBCP and Cala (LVpdP: 85 ± 46% vs 89 ± 55% vs 56 ± 26%; P = 0.30). The lactate production with EBCP was lower than with ECCP (0.6 ± 0.7 vs 1.4 ± 0.5 μmol/min; P = 0.017). The myocardial infarct size and (ECCP vs EBCP vs Cala: 16 ± 7% vs 15 ± 9% vs 24 ± 13%; P = 0.21) the ultrastructural preservation was similar in all groups. CONCLUSIONS In non-infarcted rat hearts, esmolol-based cardioplegia, particularly ECCP, offers better myocardial protection than Calafiore. After an acute myocardial infarction, cardioprotection with esmolol-based cardioplegia is similar to that with Calafiore.

scholarly journals Effect of Wenxin Granule on Ventricular Remodeling and Myocardial Apoptosis in Rats with Myocardial Infarction

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Aiming Wu ◽  
Jianying Zhai ◽  
Dongmei Zhang ◽  
Lixia Lou ◽  
Haiyan Zhu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ventricular Remodeling ◽  
Heart Function ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Tunel Staining ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Myocardial Apoptosis

Aim. To determine the effect of a Chinese herbal compound named Wenxin Granule on ventricular remodeling and myocardial apoptosis in rats with myocardial infarction (MI).Methods. Male Sprague-Dawley (SD) rats were randomly divided into four groups: the control group, the model group, the metoprolol group, and the Wenxin Granule group (WXKL group) with sample size (n) of 7 rats in each group. An MI model was established in all rats by occlusion of the left anterior descending coronary artery (the control group was without occlusion). Wenxin Granule (1.35 g/kg/day), metoprolol (12 mg/kg/day), and distilled water (5 mL/kg/day for the control and model groups) were administered orally for 4 weeks. Ultrasonic echocardiography was used to examine cardiac structural and functional parameters. Myocardial histopathological changes were observed using haematoxylin and eosin (H&E) dyeing. Myocardial apoptosis was detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) staining. Serum angiotensin II (Ang II) concentration was measured using the enzyme-linked immunosorbent assay (ELISA).Results. It was found that Wenxin Granule could partially reverse ventricular remodeling, improve heart function, alleviate the histopathological damage, inhibit myocardial apoptosis, and reduce Ang II concentration in rats with MI.Conclusions. The results of the current study suggest that Wenxin Granule may be a potential alternative and complementary medicine for the treatment of MI.

Abstract 342: Increased Myocardial Ischemic/Reperfusion Injury in Renal Failure Involves Cardiac Adiponectin Signal Deficiency

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ling Tao ◽  
Yanbin Song ◽  
Junyi Zhang ◽  
Weidong Huang ◽  
Yi Liu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Renal Failure ◽  
Cardiac Function ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Tunel Staining ◽  
Ischemic Reperfusion Injury ◽  
Ischemic Reperfusion ◽  
Nitrative Stress ◽  
Cardiovascular Morbidity And Mortality

Chronic kidney disease (CKD) is associated with increased incidence as well as adverse outcomes of acute myocardial infarction. Adiponectin (APN), known as a cardioprotective factor, has been observed decreased in cardiovascular disorders including myocardial infarction. However, plasma APN levels are significantly increased and are inversely related to the risk of cardiovascular morbidity and mortality in patients with CKD. The mechanism underlying the paradoxical relationship between high APN and poor cardiac outcome remains unclear. In the present study, subtotal nephrectomized (SN) and sham-operated mice were randomly subjected to a 30 min myocardial ischemia followed by 24 hrs reperfusion with or without human recombinant gAd treatment (2μg/g/d, 7days). Compared with sham WT mice, SN mice displayed significantly depressed cardiac function and enlarged infarct size following MI/R. TUNEL staining and caspase-3 activity assay demonstrated markedly increased cardiomyocyte apoptosis in SN mice following MI/R. What’s more, increased plasma total APN levels was observed in SN mice 4 weeks after MI/R. Importantly, SN caused further decreased cardiac function and larger infarct size in APN knockout (KO) mice compared with those in SN WT mice subjected to MI/R. However, gAd treatment significantly enhanced cardiac function and reduced infarct size and apoptosis in both WT and KO mice. Further, we found that SN KO mice showed more reduced eNOS phosphorylation, upregulated iNOS expression and ·O 2 - production and consequently increased peroxynitrite production in cardiac tissue than SN WT animals, which can be partly reversed by administration of gAd. AdipoR1 expression was reduced 4-wk after SN whereas AdipoR2 showed no significant change. More importantly, AMPK activation was also inhibited after SN and exogenous gAd supplementation reversed this change. In conclusion, the present study demonstrates that renal dysfunction increases cardiac susceptibility to ischemic/reperfusion injury, which is associated with downregulated APN/AdipoR1/AMPK signaling and increased oxidative/nitrative stress in local myocardium, and provides the first evidence for the benefits of exogenous supplement of APN on cardiac outcomes in renal failure.

scholarly journals Therapeutic Effect of Local Injection of VX765 Sodium Alginate Nanogel on Myocardial Infarction

2021 ◽  
Author(s):  
Qingxin Tian ◽  
Jianlong Liu ◽  
Qin Chen ◽  
Mingxiao Zhang
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Infarct Size ◽  
Sodium Alginate ◽  
Cardiac Fibrosis ◽  
Myocardial Infarct ◽  
Morphological Observation ◽  
Myocardial Infarct Size ◽  
Sprague Dawley

Abstract Objectives: To determine the effect of polyethyleneimine/sodium alginate composite nano-gel (AG/PEI-VX765NGs) coated with VX765 on cardiac function in rats with myocardial infarction (MI). Methods: VX765-polyethyleneimine nano-microspheres (PEI-VX765 NP) were encapsulated by sodium alginate (AG) nanogel (NGs) to construct AG/PEI-VX765 NGs. The morphological observation was performed under scanning electron microscope (SEM). The viability was evaluated by using CCK-8 assay in vitro. Then, 24 male SPF Sprague-Dawley rats were randomly divided into 4 groups: Sham, MI, PEI-VX765NP, and AG/PEI-VX765NGs. After 28 days, rats in each group were subjected to assessment of cardiac function by echocardiography. The myocardial infarct size was evaluated by TTC test, and the differences in cardiac fibrosis and cardiomyocyte apoptosis between groups were analyzed by histological methods. Results: The prepared NGs shows a porous structure, while PEI-VX765 NP is uniformly distributed in the AG NGs samples. AG/PEI-VX765 NGs with a concentration of VX765 (range: 0-1000 μM) displayed no significant toxicity to cells. Meanwhile, we observed a relatively more persistent release of VX765 from AG/PEI-VX765 NGs compared with PEI-VX765. LVIDs and LVIDd in both PEI-VX765 and AG/PEI-VX765NGs groups were significantly smaller than those in MI group, while ejection fraction (EF) and short-axis shortening rate (FS) were markedly increased in the above-mentioned two groups. Compared with MI group, PEI-VX765 and AG/PEI-VX765NGs groups exhibited a significant reduction in the infarct size, degree of fibrosis, and the rate of TUNEL positive cells. Conclusion: AG/PEI-VX765NGs can significantly improve the cardiac function of rats with MI.

Shuangxinfang prevents S100A9-induced macrophage/microglial inflammation to improve cardiac function and depression-like behaviour in rats after acute myocardial infarction

2021 ◽  
Author(s):  
Yize Sun ◽  
Zheyi Wang ◽  
Jiqiu Hou ◽  
Jinyu Shi ◽  
Zhuoran Tang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Recombinant Protein ◽  
Cardiac Function ◽  
Heart Function ◽  
Hippocampal Neurogenesis ◽  
Tunel Staining ◽  
Bv2 Cells ◽  
Microglial Inflammation

Abstract Background Depression is a common complication of cardiovascular disease, which deteriorated the cardiac function. Shuangxinfang (Psycho-cardiology Formula, PCF) was reported to alleviate myocardial ischemia injury and improve depression-like behavior. Interestingly, our previous proteomics study predicted that the protein S100A9 appeared as an important target, and macrophage/microglial inflammation might be involved in the process of PCF treating depressive disorder induced by acute myocardial infarction (AMI). The aim of this study is to validate the proteomics results. Methods AMI rat models were established in vivo, followed by the administration of PCF or ABR-215757 (also named paquinimod, inhibiting S100A9 binding to TLR4) for 5 days. Forced swimming test (FST) and open field test (OFT) were applied to record depression-like behavior, and echocardiography was employed to evaluate cardiac function. Morphological changes of cardiomyocytes were assessed by HE staining and TUNEL staining on day 7 after cardiac surgery, as well as masson trichrome staining on day 21. Hippocampal neurogenesis was determined by Nissl staining, while 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) in the hippocampus were detected as biochemical indicators of depression. Myocardial and hippocampal expression of inflammatory factors were analyzed by western blotting, immunofluorescence, and ELISA. The activation state of macrophage and microglia was assessed via immunoreaction respectively using CD68 and Iba1. For in vitro confirmation, BV2 cells were primed with recombinant protein S100A9, and then pretreated with PCF serum, to determine alterations in microglial activation and inflammation. Results Rats in the AMI group showed heart function deterioration, as well as depression-like behavior. Coronary ligation not only brought about myocardial inflammation, cell apoptosis and fibrosis, but also reduced the neurogenesis and decreased the content of 5-HT. PCF could ameliorate the pathological and phenotypic changes of the heart and brain, and inhibited the expression of S100A9/TLR4/NF-κB pathway, the activation of microglial cell and the secretion of IL-1β and TNF-α raised by AMI. ABR-215757 showed therapeutic effect and molecular biological mechanisms similar to PCF. Pretreatment with PCF serum in vitro was proved to efficiently block the hyperactivation of BV2 cells and increasement of cytokine contents induced by recombinant protein S100A9. Conclusion We identify S100A9 as a novel and potent regulator of inflammation in both heart and brain. Macrophage/microglia inflammation mediated by S100A9 is considered as a pivotal pathogenic in depression post-AMI, as well as a major pathway for the treatment of PCF, suggesting that PCF is a promising therapeutic candidate for psycho-cardiology disease.

scholarly journals Phosphatidylserine Supplementation as a Novel Strategy for Reducing Myocardial Infarct Size and Preventing Adverse Left Ventricular Remodeling

2021 ◽  
Vol 22 (9) ◽  
pp. 4401
Author(s):  
David Schumacher ◽  
Adelina Curaj ◽  
Mareike Staudt ◽  
Franziska Cordes ◽  
Andreea R. Dumitraşcu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Ventricular Remodeling ◽  
Heart Function ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Myocardial Infarct Size ◽  
Novel Strategy

Phosphatidylserines are known to sustain skeletal muscle activity during intense activity or hypoxic conditions, as well as preserve neurocognitive function in older patients. Our previous studies pointed out a potential cardioprotective role of phosphatidylserine in heart ischemia. Therefore, we investigated the effects of phosphatidylserine oral supplementation in a mouse model of acute myocardial infarction (AMI). We found out that phosphatidylserine increases, significantly, the cardiomyocyte survival by 50% in an acute model of myocardial ischemia-reperfusion. Similar, phosphatidylserine reduced significantly the infarcted size by 30% and improved heart function by 25% in a chronic model of AMI. The main responsible mechanism seems to be up-regulation of protein kinase C epsilon (PKC-ε), the main player of cardio-protection during pre-conditioning. Interestingly, if the phosphatidylserine supplementation is started before induction of AMI, but not after, it selectively inhibits neutrophil’s activation, such as Interleukin 1 beta (IL-1β) expression, without affecting the healing and fibrosis. Thus, phosphatidylserine supplementation may represent a simple way to activate a pre-conditioning mechanism and may be a promising novel strategy to reduce infarct size following AMI and to prevent myocardial injury during myocardial infarction or cardiac surgery. Due to the minimal adverse effects, further investigation in large animals or in human are soon possible to establish the exact role of phosphatidylserine in cardiac diseases.

Darbepoetin alfa, a long-acting erythropoietin analog, offers novel and delayed cardioprotection for the ischemic heart

2007 ◽  
Vol 293 (1) ◽  
pp. H60-H68 ◽  
Author(s):  
Erhe Gao ◽  
Matthieu Boucher ◽  
J. Kurt Chuprun ◽  
Rui-Hai Zhou ◽  
Andrea D. Eckhart ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Infarct Size ◽  
Darbepoetin Alfa ◽  
Caspase 3 ◽  
Ischemia Reperfusion ◽  
Tunel Staining ◽  
High Dose ◽  
Dependent Manner ◽  
Myocyte Apoptosis ◽  
Long Acting

Recent studies from our lab and others have shown that the hematopoietic cytokine erythropoietin (EPO) can protect the heart from ischemic damage in a red blood cell-independent manner. Here we examined any protective effects of the long-acting EPO analog darbepoetin alfa (DA) in a rat model of ischemia-reperfusion (I/R) injury. Rats were subjected to 30-min ischemia followed by 72-h reperfusion. In a dose-response study, DA (2, 7, 11, and 30 μg/kg) or vehicle was administered as a single bolus at the start of ischemia. To determine the time window of potential cardioprotection, a single high dose of DA (30 μg/kg) was given at either the initiation or the end of ischemia or at 1 or 24 h after reperfusion. After 3 days, cardiac function and infarct size were assessed. Acute myocyte apoptosis was quantified by TUNEL staining on myocardial sections and by caspase-3 activity assays. DA significantly reduced infarct size from 32.8 ± 3.5% (vehicle) to 11.0 ± 3.3% in a dose-dependent manner, while there was no difference in ischemic area between groups. Treatment with DA as late as 24 h after the beginning of reperfusion still demonstrated a significant reduction in infarct size (17.0 ± 1.6%). Consistent with infarction data, DA improved in vivo cardiac reserve compared with vehicle. Finally, DA significantly decreased myocyte apoptosis and caspase-3 activity after I/R. These data indicate that DA protects the heart against I/R injury and improves cardiac function, apparently through a reduction of myocyte apoptosis. Of clinical importance pointing toward a relevant therapeutic utility, we report that even if given 24 h after I/R injury, DA can significantly protect the myocardium.

scholarly journals The enhanced effect and underlying mechanisms of mesenchymal stem cells with IL-33 overexpression on myocardial infarction

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yueqiu Chen ◽  
Jianfeng Zuo ◽  
Weiqian Chen ◽  
Ziying Yang ◽  
Yanxia Zhang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Cardiac Function ◽  
Heart Function ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Therapeutic Effects ◽  
Ventricular Ejection Fraction

Abstract Background Interleukin 33 is known to have an important influence in the process of myocardial infarction, and the immunoregulatory function of MSCs could be influenced by cell factors. In this study, we evaluated the therapeutic efficacy of IL-33-overexpressing bone marrow mesenchymal stem cells (IL33-MSCs) on myocardial infarction (MI) and detected the inflammatory level and cardiac function in rats. Methods and results First, we evaluated the proliferation of T cells and polarization of macrophages that had been co-cultured with Vector-MSCs or IL33-MSCs. Co-culture experiments indicated that IL33-MSCs reduced T cell proliferation and enhanced CD206+ macrophage polarization. Second, we determined the inflammation level and cardiac function of PBS-, Vector-MSC-, and IL33-MSC-injected rats. Echocardiography indicated that left ventricular ejection fraction (LVEF) was enhanced in IL33-MSC-injected rats compared with Vector-MSC-injected rats. Postmortem analysis of rat heart tissue showed reduced fibrosis and less inflammation in IL33-MSC-injected rats. Conclusion These studies indicated that the IL33-MSC injection improved heart function and reduces inflammation in rats with MI compared with PBS or Vector-MSC injections. Graphical Abstract IL-33 overexpression enhances the immunomodulatory function and therapeutic effects of MSCs on acute MI via enhancing the polarization of macrophages toward M2, enhancing the differentiation of CD4+ T cells toward CD4+IL4+Th2 cells, and finally, reducing heart inflammation and enhancing heart function.

scholarly journals Neutrophil Elastase Deficiency Ameliorates Myocardial Injury Post Myocardial Infarction in Mice

2021 ◽  
Vol 22 (2) ◽  
pp. 722
Author(s):  
Yukino Ogura ◽  
Kazuko Tajiri ◽  
Nobuyuki Murakoshi ◽  
DongZhu Xu ◽  
Saori Yonebayashi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Neutrophil Elastase ◽  
Myocardial Injury ◽  
Flow Cytometric Analysis ◽  
Akt Signaling ◽  
Border Zone ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Deficient Mice

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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