scholarly journals IL-33 induces type-2-cytokine phenotype but exacerbates cardiac remodeling post-myocardial infarction with eosinophil recruitment, worsened systolic dysfunction, and ventricular wall rupture

2020 ◽  
Vol 134 (11) ◽  
pp. 1191-1218 ◽  
Author(s):  
Rana Ghali ◽  
Nada J. Habeichi ◽  
Abdullah Kaplan ◽  
Cynthia Tannous ◽  
Emna Abidi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Systolic Dysfunction ◽  
Cardiac Cells ◽  
Eosinophil Infiltration ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Cytokine Milieu

Abstract Myocardial infarction (MI) is the leading cause of mortality worldwide. Interleukin (IL)-33 (IL-33) is a cytokine present in most cardiac cells and is secreted on necrosis where it acts as a functional ligand for the ST2 receptor. Although IL-33/ST2 axis is protective against various forms of cardiovascular diseases, some studies suggest potential detrimental roles for IL-33 signaling. The aim of the present study was to examine the effect of IL-33 administration on cardiac function post-MI in mice. MI was induced by coronary artery ligation. Mice were treated with IL-33 (1 μg/day) or vehicle for 4 and 7 days. Functional and molecular changes of the left ventricle (LV) were assessed. Single cell suspensions were obtained from bone marrow, heart, spleen, and peripheral blood to assess the immune cells using flow cytometry at 1, 3, and 7 days post-MI in IL-33 or vehicle-treated animals. The results of the present study suggest that IL-33 is effective in activating a type 2 cytokine milieu in the damaged heart, consistent with reduced early inflammatory and pro-fibrotic response. However, IL-33 administration was associated with worsened cardiac function and adverse cardiac remodeling in the MI mouse model. IL-33 administration increased infarct size, LV hypertrophy, cardiomyocyte death, and overall mortality rate due to cardiac rupture. Moreover, IL-33-treated MI mice displayed a significant myocardial eosinophil infiltration at 7 days post-MI when compared with vehicle-treated MI mice. The present study reveals that although IL-33 administration is associated with a reparative phenotype following MI, it worsens cardiac remodeling and promotes heart failure.

Abstract P109: Spiny Mice Are Protected From Myocardial Infarction Induced Cardiac Pathophysiology

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
YanFei Qi ◽  
Juan Zhang ◽  
Lei Wang ◽  
Ashok Kumar ◽  
Avinash Mandloi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Infarct Size ◽  
Tissue Injury ◽  
Fold Increase ◽  
Cardiac Cells ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Spiny Mice ◽  
Cd1 Mice

Background: Despite the advancement in drug and surgical interventions, myocardial damage and associated cardiac dysfunction lead to heart failure that remains common cause of death following myocardial infarction (MI). Spiny mice (Acomys cahirinus, SM) have been shown to possess regenerating capacity following deep tissue injury without scarring ( Nature 2013 ). This led us to investigate if this regenerative property would also be preserved in the heart. Methods and Results: Adult CD1 and SM were subject to left anterior descending coronary artery ligation or sham surgeries. Proliferative cells were identified by nuclear incorporation of 5-bromodeoxyuridine (BrdU, daily, i.p.) and injection was started from 3d post MI continued to 2wks post MI. Cardiac function was assessed using echocardiography and MRI. SM exhibited 3-fold smaller infarct size (SM-MI 18.6±3.4% vs CD1-MI 76.2±3.4%, p<0.05) and better contractility measured by ejection fraction (SM-MI 77.1±6.5 vs CD1-MI 24.6±4.6, %, p<0.05) than CD1 mice. SM showed 6-fold increase in BrdU + cells in left ventricle after MI while CD1 mice had 4-fold increase (CD1-sham 11±3.5 vs CD1-MI 44±9.1 and SM-sham 16±9.8 vs SM-MI 101.1±30.9, p<0.05). Though basal cardiac ACE2 activity was not different between CD1 and SM, MI resulted in a 16% decrease in cardiac ACE2 activity in CD1-MI mice but 20% elevation of cardiac ACE2 activity in myocardial tissue in SM-MI. Conclusions: SM are protected from ischemia induced cardiac damage and dysfunction. This involves increased proliferating cardiac cells and reduction in infarct size. Thus SM could be an ideal animal model for identification of molecular and genetic circuits involved in preservation/regeneration of cardiac function with translational implication to human MI.

scholarly journals Impact of BDNF Val66Met Polymorphism on Myocardial Infarction: Exploring the Macrophage Phenotype

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1084 ◽  
Author(s):  
Leonardo Sandrini ◽  
Laura Castiglioni ◽  
Patrizia Amadio ◽  
José Pablo Werba ◽  
Sonia Eligini ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Peritoneal Macrophages ◽  
Coronary Artery Ligation ◽  
Macrophage Phenotype ◽  
Nucleotide Polymorphism ◽  
Artery Ligation ◽  
Single Nucleotide ◽  
Val66met Polymorphism ◽  
Bdnf Val66met Polymorphism

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin growth factor family, well known for its role in the homeostasis of the cardiovascular system. Recently, the human BDNF Val66Met single nucleotide polymorphism has been associated with the increased propensity for arterial thrombosis related to acute myocardial infarction (AMI). Using cardiac magnetic resonance imaging and immunohistochemistry analyses, we showed that homozygous mice carrying the human BDNF Val66Met polymorphism (BDNFMet/Met) undergoing left anterior descending (LAD) coronary artery ligation display an adverse cardiac remodeling compared to wild-type (BDNFVal/Val). Interestingly, we observed a persistent presence of pro-inflammatory M1-like macrophages and a reduced accumulation of reparative-like phenotype macrophages (M2-like) in the infarcted heart of mutant mice. Further qPCR analyses showed that BDNFMet/Met peritoneal macrophages are more pro-inflammatory and have a higher migratory ability compared to BDNFVal/Val ones. Finally, macrophages differentiated from circulating monocytes isolated from BDNFMet/Met patients with coronary heart disease displayed the same pro-inflammatory characteristics of the murine ones. In conclusion, the BDNF Val66Met polymorphism predisposes to adverse cardiac remodeling after myocardial infarction in a mouse model and affects macrophage phenotype in both humans and mice. These results provide a new cellular mechanism by which this human BDNF genetic variant could influence cardiovascular disease.

Effects of carbon nanotube-mediated Caspase3 gene silencing on cardiomyocyte apoptosis and cardiac function during early acute myocardial infarction

Nanoscale ◽  
2020 ◽  
Vol 12 (42) ◽  
pp. 21599-21604
Author(s):  
Yi Li ◽  
Hong Yu ◽  
Liang Zhao ◽  
Yuting Zhu ◽  
Rui Bai ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Gene Silencing ◽  
Ventricular Remodeling ◽  
Myocardial Cell ◽  
Coronary Artery Ligation ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Artery Ligation ◽  
Sd Rats

Caspase3 gene silencing based on the gene transfer carrier F-CNT-siCas3 had obvious protective effects on myocardial cell apoptosis, ventricular remodeling, and cardiac function in Sprague-Dawley (SD) rats after coronary artery ligation.

Depletion of cardiac 14-3-3η protein adversely influences pathologic cardiac remodeling during myocardial infarction after coronary artery ligation in mice

2016 ◽  
Vol 202 ◽  
pp. 146-153 ◽  
Author(s):  
Remya Sreedhar ◽  
Somasundaram Arumugam ◽  
Rajarajan A. Thandavarayan ◽  
Vijayasree V. Giridharan ◽  
Vengadeshprabhu Karuppagounder ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Cardiac Remodeling ◽  
Coronary Artery Ligation ◽  
Artery Ligation

scholarly journals Clofibrate Treatment Decreases Inflammation and Reverses Myocardial Infarction-Induced Remodelation in a Rodent Experimental Model

Molecules ◽  
2019 ◽  
Vol 24 (2) ◽  
pp. 270 ◽  
Author(s):  
Luz Ibarra-Lara ◽  
María Sánchez-Aguilar ◽  
Elizabeth Soria-Castro ◽  
Jesús Vargas-Barrón ◽  
Francisco Roldán ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Cardiac Remodeling ◽  
Ventricular Remodeling ◽  
Ex Vivo ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Cardiac Damage ◽  
Artery Ligation ◽  
Apoptotic Proteins

Myocardial infarction (MI) initiates an inflammatory response that promotes both beneficial and deleterious effects. The early response helps the myocardium to remove damaged tissue; however, a prolonged later response brings cardiac remodeling characterized by functional, metabolic, and structural pathological changes. Current pharmacological treatments have failed to reverse ischemic-induced cardiac damage. Therefore, our aim was to study if clofibrate treatment was capable of decreasing inflammation and apoptosis, and reverse ventricular remodeling and MI-induced functional damage. Male Wistar rats were assigned to (1) Sham coronary artery ligation (Sham) or (2) Coronary artery ligation (MI). Seven days post-MI, animals were further divided to receive vehicle (V) or clofibrate (100 mg/kg, C) for 7 days. The expression of IL-6, TNF-α, and inflammatory related molecules ICAM-1, VCAM-1, MMP-2 and -9, nuclear NF-kB, and iNOS, were elevated in MI-V. These inflammatory biomarkers decreased in MI-C. Also, apoptotic proteins (Bax and pBad) were elevated in MI-V, while clofibrate augmented anti-apoptotic proteins (Bcl-2 and 14-3-3ε). Clofibrate also protected MI-induced changes in ultra-structure. The ex vivo evaluation of myocardial functioning showed that left ventricular pressure and mechanical work decreased in infarcted rats; clofibrate treatment raised those parameters to control values. Echocardiogram showed that clofibrate partially reduced LV dilation. In conclusion, clofibrate decreases cardiac remodeling, decreases inflammatory molecules, and partly preserves myocardial diameters.

Targeted inhibition of activin receptor-like kinase 5 signaling attenuates cardiac dysfunction following myocardial infarction

2010 ◽  
Vol 298 (5) ◽  
pp. H1415-H1425 ◽  
Author(s):  
Sih Min Tan ◽  
Yuan Zhang ◽  
Kim A. Connelly ◽  
Richard E. Gilbert ◽  
Darren J. Kelly
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Dysfunction ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Type I ◽  
Artery Ligation ◽  
Receptor Like Kinase

Following myocardial infarction (MI), the heart undergoes a pathological process known as remodeling, which in many instances results in cardiac dysfunction and ultimately heart failure and death. Transforming growth factor-β (TGF-β) is a key mediator in the pathogenesis of cardiac remodeling following MI. We thus aimed to inhibit TGF-β signaling using a novel orally active TGF-β type I receptor [activin receptor-like kinase 5 (ALK5)] inhibitor (GW788388) to attenuate left ventricular remodeling and cardiac dysfunction in a rat model of MI. Sprague-Dawley rats underwent left anterior descending coronary artery ligation to induce experimental MI and then were randomized to receive GW788388 at a dosage of 50 mg·kg−1·day−1 or vehicle 1 wk after surgery. After 4 wk of treatment, echocardiography was performed before the rats were euthanized. Animals that received left anterior descending coronary artery ligation demonstrated systolic dysfunction, Smad2 activation, myofibroblasts accumulation, collagen deposition, and myocyte hypertrophy (all P < 0.05). Treatment with GW788388 significantly attenuated systolic dysfunction in the MI animals, together with the attenuation of the activated (phosphorylated) Smad2 ( P < 0.01), α-smooth muscle actin ( P < 0.001), and collagen I ( P < 0.05) in the noninfarct zone of MI rats. Cardiomyocyte hypertrophy in MI hearts was also attenuated by ALK5 inhibition ( P < 0.05). In brief, treatment with a novel TGF-β type I receptor inhibitor, GW788388, significantly reduced TGF-β activity, leading to the attenuation of systolic dysfunction and left ventricular remodeling in an experimental rat model of MI.

scholarly journals Aucubin Protects against Myocardial Infarction-Induced Cardiac Remodeling via nNOS/NO-Regulated Oxidative Stress

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Zheng Yang ◽  
Qing-Qing Wu ◽  
Yang Xiao ◽  
Ming Xia Duan ◽  
Chen Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Coronary Artery Ligation ◽  
No Production ◽  
Protective Effects ◽  
Artery Ligation ◽  
Nos Inhibitors

Whether aucubin could protect myocardial infarction- (MI-) induced cardiac remodeling is not clear. In this study, in a mouse model, cardiac remodeling was induced by left anterior descending coronary artery ligation surgery. Mice were intraperitoneally injected with aucubin (10 mg/kg) 3 days post-MI. Two weeks post-MI, mice in the aucubin treatment group showed decreased mortality, decreased infarct size, and improved cardiac function. Aucubin also decreased cardiac remodeling post-MI. Consistently, aucubin protected cardiomyocytes against hypoxic injury in vitro. Mechanistically, we found that aucubin inhibited the ASK1/JNK signaling. These effects were abolished by the JNK activator. Moreover, we found that the oxidative stress was attenuated in both in vivo aucubin-treated mice heart and in vitro-treated cardiomyocytes, which caused decreased thioredoxin (Trx) consumption, leading to ASK1 forming the inactive complex with Trx. Aucubin increased nNOS-derived NO production in vivo and vitro. The protective effects of aucubin were reversed by the NOS inhibitors L-NAME and L-VINO in vitro. Furthermore, nNOS knockout mice also reversed the protective effects of aucubin on cardiac remodeling. Taken together, aucubin protects against cardiac remodeling post-MI through activation of the nNOS/NO pathway, which subsequently attenuates the ROS production, increases Trx preservation, and leads to inhibition of the ASK1/JNK pathway.

scholarly journals β1-Adrenergic receptors stimulate cardiac contractility and CaMKII activation in vivo and enhance cardiac dysfunction following myocardial infarction

2009 ◽  
Vol 297 (4) ◽  
pp. H1377-H1386 ◽  
Author(s):  
ByungSu Yoo ◽  
Anthony Lemaire ◽  
Supachoke Mangmool ◽  
Matthew J. Wolf ◽  
Antonio Curcio ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cardiac Contractility ◽  
Border Zone ◽  
Tunel Staining ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Cardiac Inotropy ◽  
Significant Attenuation

The β-adrenergic receptor (βAR) signaling system is one of the most powerful regulators of cardiac function and a key regulator of Ca2+ homeostasis. We investigated the role of βAR stimulation in augmenting cardiac function and its role in the activation of Ca2+/calmodulin-dependent kinase II (CaMKII) using various βAR knockouts (KO) including β1ARKO, β2ARKO, and β1/β2AR double-KO (DKO) mice. We employed a murine model of left anterior descending coronary artery ligation to examine the differential contributions of specific βAR subtypes in the activation of CaMKII in vivo in failing myocardium. Cardiac inotropy, chronotropy, and CaMKII activity following short-term isoproterenol stimulation were significantly attenuated in β1ARKO and DKO compared with either the β2ARKO or wild-type (WT) mice, indicating that β1ARs are required for catecholamine-induced increases in contractility and CaMKII activity. Eight weeks after myocardial infarction (MI), β1ARKO and DKO mice showed a significant attenuation in fractional shortening compared with either the β2ARKO or WT mice. CaMKII activity after MI was significantly increased only in the β2ARKO and WT hearts and not in the β1ARKO and DKO hearts. The border zone of the infarct in the β2ARKO and WT hearts demonstrated significantly increased apoptosis by TUNEL staining compared with the β1ARKO and DKO hearts. Taken together, these data show that cardiac function and CaMKII activity are mediated almost exclusively by the β1AR. Moreover, it appears that β1AR signaling is detrimental to cardiac function following MI, possibly through activation of CaMKII.

Abstract 162: c-fos Protects the Myocardium from Ischemic Injury and Improves Cardiac Function

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Xiangru Lu ◽  
Ming Lei ◽  
Fuli Xiang ◽  
Qingping Feng
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Infarct Size ◽  
Ischemic Injury ◽  
Coronary Artery Ligation ◽  
Area At Risk ◽  
Artery Ligation ◽  
Protein Ratio ◽  
Myocardial Apoptosis ◽  
Bax Protein

Background: c-fos is an immediate early response gene. c-Fos proteins form heterodimers with Jun family proteins, and the resulting AP-1 complexes regulate transcription by binding to the AP-1 sequence found in many cellular genes. c-fos is activated in cardiomyocytes following myocardial infarction. However, the role of c-fos in regulating cardiomyocyte survival and cardiac function post myocardial infarction (MI) is not known. In the present study, we hypothesized that c-fos protects the myocardium from ischemic injury and improves cardiac function. Methods and Results: The generation of mice with cardiomyocyte specific c-fos −/ − was achieved by crossing the floxed c-fos mice with mice over-expressing Cre recombinase under the control of α-myosin heavy chain. Wild-type (WT) littermates were used as controls. MI was induced by coronary artery ligation. Infarct size, myocardial apoptosis and cardiac function were determined at 2 days post-MI. While area at risk was similar between the 2 groups, infarct size was significantly increased in c-fos −/ − compared to WT mice (58 ± 4% vs. 44 ± 3%, P< 0.05). Myocardial caspase-3 activity and cytosolic DNA fragments in the peri-infarct region were significantly increased while Bcl-2/Bax protein ratio was significantly decreased in c-fos −/− mice ( P< 0.05). LV pressure volume relationship was assessed in vivo using a Millar pressure conductance catheter. LV end-systolic elastance ( E es ) and +d P /dt max were significantly decreased in c-fos −/− compared to WT mice (1.7 ± 0.4 vs. 5.1 ± 1.0 mmHg/μL; 4776 ± 567 vs. 7006 ± 319 mmHg/s, P< 0.01). Conclusions: Deficiency in c-fos increases infarct size and myocardial apoptosis leading to impaired cardiac function post-MI. Our results suggest that c-fos protects the myocardium from ischemic injury and improves cardiac function.

scholarly journals Anti-CCL21 Antibody Attenuates Infarct Size and Improves Cardiac Remodeling After Myocardial Infarction

2015 ◽  
Vol 37 (3) ◽  
pp. 979-990 ◽  
Author(s):  
Yi Jiang ◽  
Jianwen Bai ◽  
Lunxian Tang ◽  
Pei Zhang ◽  
Jun Pu
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Cardiac Remodeling ◽  
Immune Cell ◽  
Serum Levels ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Cell Recruitment ◽  
Immune Cell Recruitment

Background/Aims: Over-activation of cellular inflammatory effectors adversely affects myocardial function after acute myocardial infarction (AMI). The CC-chemokine CCL21 is, via its receptor CCR7, one of the key regulators of inflammation and immune cell recruitment, participates in various inflammatory disorders, including cardiovascular ones. This study explored the therapeutic effect of an anti-CCL21 antibody in cardiac remodeling after myocardial infarction. Methods and Results: An animal model of AMI generated by left anterior descending coronary artery ligation in C57BL/6 mice resulted in higher levels of circulating CCL21 and cardiac CCR7. Neutralization of CCL21 by intravenous injection of anti-CCL21 monoclonal antibody reduced infarct size after AMI, decreased serum levels of neutrophil and monocyte chemo attractants post AMI, diminished neutrophil and macrophage recruitment in infarcted myocardium, and suppressed MMP-9 and total collagen content in myocardium. Anti-CCL21 treatment also limited cardiac enlargement and improved left ventricular function. Conclusions: Our study indicated that CCL21 was involved in cardiac remodeling post infarction and anti-CCL21 strategies might be useful in the treatment of AMI.

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