scholarly journals Nitroxides Mitigate Neutrophil-Mediated Damage to the Myocardium after Experimental Myocardial Infarction in Rats

2020 ◽  
Vol 21 (20) ◽  
pp. 7650
Author(s):  
Mary El Kazzi ◽  
Han Shi ◽  
Sally Vuong ◽  
Xiaosuo Wang ◽  
Belal Chami ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Hypochlorous Acid ◽  
Immune Cell ◽  
Reperfusion Therapy ◽  
Experimental Myocardial Infarction ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Post Surgery ◽  
Male Wistar Rats ◽  
Oxidant Production

Reperfusion therapy increases survival post-acute myocardial infarction (AMI) while also stimulating secondary oxidant production and immune cell infiltration. Neutrophils accumulate within infarcted myocardium within 24 h post-AMI and release myeloperoxidase (MPO) that catalyses hypochlorous acid (HOCl) production while increasing oxidative stress and inflammation, thereby enhancing ventricular remodelling. Nitroxides inhibit MPO-mediated HOCl production, potentially ameliorating neutrophil-mediated damage. Aim: Assess the cardioprotective ability of nitroxide 4-methoxyTEMPO (4MetT) within the setting of AMI. Methods: Male Wistar rats were separated into 3 groups: SHAM, AMI/R, and AMI/R + 4MetT (15 mg/kg at surgery via oral gavage) and subjected to left descending coronary artery ligation for 30 min to generate an AMI, followed by reperfusion. One cohort of rats were sacrificed at 24 h post-reperfusion and another 28 days post-surgery (with 4MetT (15 mg/kg) administration twice daily). Results: 3-chlorotyrosine, a HOCl-specific damage marker, decreased within the heart of animals in the AMI/R + 4-MetT group 24 h post-AMI, indicating the drug inhibited MPO activity; however, there was no evident difference in either infarct size or myocardial scar size between the groups. Concurrently, MPO, NfκB, TNFα, and the oxidation marker malondialdehyde increased within the hearts, with 4-MetT only demonstrating a trend in decreasing MPO and TNF levels. Notably, 4MetT provided a significant improvement in cardiac function 28 days post-AMI, as assessed by echocardiography, indicating potential for 4-MetT as a treatment option, although the precise mechanism of action of the compound remains unclear.

scholarly journals Pamidronate Attenuates Diastolic Dysfunction Induced by Myocardial Infarction Associated with Changes in Geometric Patterning

2015 ◽  
Vol 35 (1) ◽  
pp. 259-269 ◽  
Author(s):  
Andréa F. Gonçalves ◽  
Luiz Henrique Congio ◽  
Priscila P. dos Santos ◽  
Bruna P. M. Rafacho ◽  
Bruna L. B. Pereira ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Diastolic Dysfunction ◽  
Subcutaneous Injection ◽  
Sham Group ◽  
Ventricular Remodeling ◽  
Systolic Function ◽  
Calcium Handling ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Male Wistar Rats

Background/Aims: The aim of this study was to evaluate the influence of pamidronate on ventricular remodeling after myocardial infarction. Methods: Male Wistar rats were assigned to four groups: a sham group, in which animals were submitted to simulated surgery and received weekly subcutaneous injection of saline (S group; n=14); a group in which animals received weekly subcutaneous injection of pamidronate (3 mg/kg of body weight) and were submitted to simulated surgery (SP group, n=14); a myocardial infarction group, in which animals were submitted to coronary artery ligation and received weekly subcutaneous injection of saline (MI group, n=13); and a myocardial infarction group with pamidronate treatment (MIP group, n=14). The rats were observed for three months. Results: Animals submitted to MI had left chamber enlargement and worse diastolic and systolic function compared with SHAM groups. E/A ratio, LV posterior and relative wall thickness were lower in the MIP compared with the MI group. There was no interaction between pamidronate administration and MI on systolic function, myocyte hypertrophy, collagen content, and calcium handling proteins. Conclusion: Pamidronate attenuates diastolic dysfunction following MI.

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.

Myocardial expression of PDECGF is associated with extracellular matrix remodeling in experimental myocardial infarction in rats

2010 ◽  
Vol 88 (3) ◽  
pp. 491-503 ◽  
Author(s):  
Thiagarajan Hemalatha ◽  
Chidambaram Balachandran ◽  
Bhakthavatsalam Murali Manohar ◽  
Mohammed Nayeem ◽  
Samu Subramaniam ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Extracellular Matrix ◽  
Experimental Myocardial Infarction ◽  
Border Region ◽  
Coronary Artery Ligation ◽  
Matrix Remodeling ◽  
Rt Pcr ◽  
Artery Ligation ◽  
Ecm Remodeling ◽  
Tnf Α

Platelet-derived endothelial cell growth factor (PDECGF) is a potent angiogenic peptide with anti-apoptotic activity expressed widely in tumours. However, its expression in myocardial infarction (MI) is not yet established. This study aimed to assess the myocardial expression of PDECGF in rats after MI. Extracellular matrix (ECM) remodeling plays an important role in angiogenesis; hence, changes in the ECM components were investigated in the myocardium after MI, which was induced in rats by coronary artery ligation (CAL) and verified using biochemical markers and histopathology. Immunohistochemistry, RT-PCR, and activity assays identified the expression pattern of PDECGF on days 1, 2, 4, 8, 16, and 32 after CAL. The levels of TNF-α, MMP-2, collagen, and glycosaminoglycans in the ECM were assessed. Studies on immunohistochemistry, RT-PCR, and PDECGF activity demonstrated elevated levels of PDECGF expression from day 2 after CAL. Macrophages, endothelial cells, fibroblasts, and cardiomyocytes, especially at the border region of the lesion, showed an enhanced expression for PDECGF. Remodeling of the ECM was depicted by changes in the levels of TNF-α, MMP-2, collagen, and GAG. Hence, this study clearly indicated PDECGF as an important angiogenic molecule expressed during MI and the alterations in ECM components facilitated the process of angiogenesis.

scholarly journals Protective effects of Salidroside on cardiac function in mice with myocardial infarction

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Pengsheng Chen ◽  
Jia Liu ◽  
Hongyun Ruan ◽  
Miaomiao Zhang ◽  
Peng Wu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Normal Saline ◽  
Myocardial Inflammation ◽  
Coronary Artery Ligation ◽  
Protective Effects ◽  
Myocardial Remodeling ◽  
Artery Ligation ◽  
Post Surgery

AbstractSalidroside (SAL) is the major ingredient of Rhodiola rosea, and has been traditionally used in Chinese medicine for decades. Numerous studies have demonstrated the protective effects of SAL for myocardial ischemia. However, it is yet to be deciphered whether SAL has cardioprotective effects after myocardial infarction (MI) in vivo. In the present study, we established a mouse MI model via coronary artery ligation. The aim was to investigate whether SAL treatment could reduce mortality, improve cardiac function and attenuate myocardial remodeling in MI mice. Post-surgery, mice were randomly administered SAL or normal saline. After 21 days, SAL was found to significantly reduce mortality, improve cardiac function, reduce fibrosis and infarct size compared to normal saline. In addition, oral administration of SAL could attenuate myocardial inflammation and apoptosis and promote angiogenesis. SAL down-regulated the expression levels of TNF-α, TGF-β1, IL-1β, Bax and up-regulate the expression of Bcl-2, VEGF, Akt and eNOS. These results indicated that SAL could alleviate the pathological processes of myocardial remodeling in MI mice, and may be a potentially effective therapeutic approach for the management of clinical ischemic cardiovascular diseases.

scholarly journals Exercise Training Stabilizes RyR2-Dependent Ca2+ Release in Post-infarction Heart Failure

2021 ◽  
Vol 7 ◽  
Author(s):  
Tore Kristian Danielsen ◽  
Mani Sadredini ◽  
Ravinea Manotheepan ◽  
Jan Magnus Aronsen ◽  
Michael Frisk ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Exercise Training ◽  
Radioligand Binding ◽  
Left Ventricular ◽  
Post Myocardial Infarction ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Ventricular Cardiomyocytes ◽  
Male Wistar Rats

Aim: Dysfunction of the cardiac ryanodine receptor (RyR2) is an almost ubiquitous finding in animal models of heart failure (HF) and results in abnormal Ca2+ release in cardiomyocytes that contributes to contractile impairment and arrhythmias. We tested whether exercise training (ET), as recommended by current guidelines, had the potential to stabilize RyR2-dependent Ca2+ release in rats with post-myocardial infarction HF.Materials and Methods: We subjected male Wistar rats to left coronary artery ligation or sham operations. After 1 week, animals were characterized by echocardiography and randomized to high-intensity interval ET on treadmills or to sedentary behavior (SED). Running speed was adjusted based on a weekly VO2max test. We repeated echocardiography after 5 weeks of ET and harvested left ventricular cardiomyocytes for analysis of RyR2-dependent systolic and spontaneous Ca2+ release. Phosphoproteins were analyzed by Western blotting, and beta-adrenoceptor density was quantified by radioligand binding.Results: ET increased VO2max in HF-ET rats to 127% of HF-SED (P < 0.05). This coincided with attenuated spontaneous SR Ca2+ release in left ventricular cardiomyocytes from HF-ET but also reduced Ca2+ transient amplitude and slowed Ca2+ reuptake during adrenoceptor activation. However, ventricular diameter and fractional shortening were unaffected by ET. Analysis of Ca2+ homeostasis and major proteins involved in the regulation of SR Ca2+ release and reuptake could not explain the attenuated spontaneous SR Ca2+ release or reduced Ca2+ transient amplitude. Importantly, measurements of beta-adrenoceptors showed a normalization of beta1-adrenoceptor density and beta1:beta2-adrenoceptor ratio in HF-ET.Conclusion: ET increased aerobic capacity in post-myocardial infarction HF rats and stabilized RyR2-dependent Ca2+ release. Our data show that these effects of ET can be gained without major alterations in SR Ca2+ regulatory proteins and indicate that future studies should include upstream parts of the sympathetic signaling pathway.

scholarly journals Natural Heart Regeneration in a Neonatal Rat Myocardial Infarction Model

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 229 ◽  
Author(s):  
Hanjay Wang ◽  
Michael J. Paulsen ◽  
Camille E. Hironaka ◽  
Hye Sook Shin ◽  
Justin M. Farry ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Circulatory Arrest ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Coronary Artery Ligation ◽  
Heart Regeneration ◽  
Newborn Rats ◽  
Artery Ligation ◽  
Newborn Mice ◽  
Post Surgery

Newborn mice and piglets exhibit natural heart regeneration after myocardial infarction (MI). Discovering other mammals with this ability would provide evidence that neonatal cardiac regeneration after MI may be a conserved phenotype, which if activated in adults could open new options for treating ischemic cardiomyopathy in humans. Here, we hypothesized that newborn rats undergo natural heart regeneration after MI. Using a neonatal rat MI model, we performed left anterior descending coronary artery ligation or sham surgery in one-day-old rats under hypothermic circulatory arrest (n = 74). Operative survival was 97.3%. At 1 day post-surgery, rats in the MI group exhibited significantly reduced ejection fraction (EF) compared to shams (87.1% vs. 53.0%, p < 0.0001). At 3 weeks post-surgery, rats in the sham and MI groups demonstrated no difference in EF (71.1% vs. 69.2%, respectively, p = 0.2511), left ventricular wall thickness (p = 0.9458), or chamber diameter (p = 0.7801). Masson’s trichome and picrosirius red staining revealed minimal collagen scar after MI. Increased numbers of cardiomyocytes positive for 5-ethynyl-2′-deoxyuridine (p = 0.0072), Ki-67 (p = 0.0340), and aurora B kinase (p = 0.0430) were observed within the peri-infarct region after MI, indicating ischemia-induced cardiomyocyte proliferation. Overall, we present a neonatal rat MI model and demonstrate that newborn rats are capable of endogenous neocardiomyogenesis after MI.

Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction

2003 ◽  
Vol 285 (3) ◽  
pp. H1229-H1235 ◽  
Author(s):  
Shunji Hayashidani ◽  
Hiroyuki Tsutsui ◽  
Masaki Ikeuchi ◽  
Tetsuya Shiomi ◽  
Hidenori Matsusaka ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Left Ventricular ◽  
Experimental Myocardial Infarction ◽  
Matrix Metalloproteinase 2 ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Targeted Deletion ◽  
Arterial Blood ◽  
Lv Remodeling

Matrix metalloproteinase-2 (MMP-2) is prominently overexpressed both after myocardial infarction (MI) and in heart failure. However, its pathophysiological significance in these conditions is still unclear. We thus examined the effects of targeted deletion of MMP-2 on post-MI left ventricular (LV) remodeling and failure. Anterior MI was produced in 10- to 12-wk-old male MMP-2 knockout (KO) and sibling wild-type (WT) mice by ligating the left coronary artery. By day 28, MI resulted in a significant increase in mortality in association with LV cavity dilatation and dysfunction. The MMP-2 KO mice had a significantly better survival rate than WT mice (56% vs. 85%, P < 0.05), despite a comparable infarct size (50 ± 3% vs. 51 ± 3%, P = not significant), heart rate, and arterial blood pressure. The KO mice had a significantly lower incidence of LV rupture (10% vs. 39%, P < 0.05), which occurred within 7 days of MI. The KO mice exerted less LV cavity dilatation and improved fractional shortening after MI by echocardiography. The LV zymographic MMP-2 level significantly increased in WT mice after coronary artery ligation; however, this was completely prevented in KO mice. In contrast, the increase in the LV zymographic MMP-9 level after MI was similar between KO and WT mice. MMP-2 activation is therefore considered to contribute to an early cardiac rupture as well as late LV remodeling after MI. The inhibition of MMP-2 activation may therefore be a potentially useful therapeutic strategy to manage post-MI hearts.

scholarly journals Single-cell RNA Sequencing Reveals the Temporal Diversity and Dynamics of Cardiac Immunity after Myocardial Infarction

2021 ◽  
Author(s):  
Kaiyu Jin ◽  
Shan Gao ◽  
Penghui Yang ◽  
Rongfang Guo ◽  
Dan Li ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Single Cell ◽  
Rna Sequencing ◽  
Immune Cell ◽  
Inflammatory Factors ◽  
Coronary Artery Ligation ◽  
Sequencing Analysis ◽  
Artery Ligation ◽  
Single Cell Rna Sequencing ◽  
Time Specific

Myocardial infarction (MI) is strongly associated with the temporal regulation of cardiac immunity. However, a variety of current clinical trials have failed because of the lack of post-MI immunomodulating/anti-inflammatory targets. We performed single-cell RNA sequencing analysis of cardiac Cd45+ immune cell at 0, 3, 7, and 14 days after injury in a mouse left anterior descending coronary artery ligation model. Major immune cell populations, distinct subsets, and dynamic changes were identified. Macrophages (Mϕ)/monocytes were most abundant, peaking at 3 days after infarction. Mϕ-5 and Mϕ-6 were the predominant infiltrated subsets at this time point, with strong expression of inflammatory factors. Further analysis demonstrated that suppressing these sets attenuated pathological MI progression by preventing subsequent leukocyte extravasation and adverse remodeling. We also detected abundant apoptotic neutrophils and a profibrotic macrophage subset on days 7 and 14 respectively. These results provide a basis for developing cell type- and time-specific interventions in MI.

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