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.

scholarly journals LRRK2 Deficiency Protects Hearts from Myocardial Infarction Injury in Mice via the P53/HMGB1 Pathway

2021 ◽  
Author(s):  
Yuan Liu ◽  
Changgui Chen ◽  
Lu Chen ◽  
Xiaoxin Pei ◽  
Zekai Tao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Coronary Artery Ligation ◽  
Wild Type ◽  
Artery Ligation ◽  
Rat Cardiomyocytes ◽  
Ventricular Fibrosis ◽  
Deficient Mice

Abstract Purpose: LRRK2 is a Ser/Thr kinase with multiple functional domains. Current studies have shown that its mutations are closely related to hereditary Parkinson's disease. However, its role in cardiovascular disease, especially in myocardial infarction, is unclear. The aim of this study was to explore the functional role of LRRK2 in myocardial infarction. Methods: Wild-type and LRRK2 knockout mice were subjected to coronary artery ligation (left anterior descent) to establish a myocardial infarction mouse model. Neonatal rat cardiomyocytes were subjected to hypoxia to induce hypoxia injury in vitro. Results: We found increased LRRK2 expression levels in the infarct periphery of mouse hearts and hypoxic cardiomyocytes. LRRK2-deficient mice exhibited a decreased death rate and reduced infarction area compared to the wild-type controls 14 days after infarction. LRRK2-deficient mice showed reduced left ventricular fibrosis and inflammatory response, as well as improved cardiac function. In the in vitro study, LRRK2 silencing decreased the cleaved-caspase3 activity, reduced cardiomyocyte apoptosis, and diminished hypoxia-induced inflammation. However, LRRK2 overexpression enhanced the cleaved-caspase3 activity, increased the number of apoptotic cardiomyocytes, and caused remarkable hypoxia-induced inflammation. When exploring the related underlying mechanisms, we found that hypoxia induced an increase in HIFα expression, which enhanced LRRK2 expression. LRRK2 induced high expression of HMGB1 via P53. When blocking HMGB1 using the anti-HMGB1 antibody, the deteriorating effects caused by LRRK2 overexpression following hypoxia were inhibited in cardiomyocytes.Conclusions: In summary, LRRK2 deficiency protects hearts from myocardial infarction injury. The mechanism underlying this phenomenon involves the P53-HMGB1 pathway.

Cardiac adaptations to endurance training in rats with a chronic myocardial infarction

1989 ◽  
Vol 66 (2) ◽  
pp. 712-719 ◽  
Author(s):  
T. I. Musch ◽  
R. L. Moore ◽  
P. G. Smaldone ◽  
M. Riedy ◽  
R. Zelis
Keyword(s):  
Myocardial Infarction ◽  
Endurance Training ◽  
Left Ventricular ◽  
Treadmill Running ◽  
Coronary Artery Ligation ◽  
Maximal Heart Rate ◽  
Chronic Myocardial Infarction ◽  
Artery Ligation ◽  
Training Paradigm ◽  
Myosin Isozyme

The hemodynamic response to maximal exercise was determined in sedentary and trained rats with a chronic myocardial infarction (MI) produced by coronary artery ligation and in rats that underwent sham operations (SHAM). Infarct size in the MI groups of rats comprised 28–29% of the total left ventricle and resulted in both metabolic and hemodynamic changes that suggested that these animals had moderate compensated heart failure. The training regimen used in the present study produced significant increases in maximal O2 uptake (VO2max) when expressed in absolute terms (ml/min) or when normalized for body weight (ml.min-1.kg-1) and consisted of treadmill running at work loads that were equivalent to 70–80% of the animal's VO2max for a period of 60 min/day, 5 days/wk over an 8- to 10-wk interval. This training paradigm produced two major cardiocirculatory adaptations in the MI rat that had not been elicited previously when using a training paradigm of a lower intensity. First, the decrement in the maximal heart rate response to exercise (known as “chronotropic incompetence”) found in the sedentary MI rat was completely reversed by endurance training. Second, the downregulation of cardiac myosin isozyme composition from the fast ATPase V1 isoform toward the slower ATPase (V2 and V3) isoforms in the MI rat was partially reversed by endurance training. These cardiac adaptations occurred without a significant increase in left ventricular pump function as an increase in maximal cardiac output (Qmax) and maximal stroke volume (SVmax) did not occur in the trained MI rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of Myocardial Infarction with Sequential Ligation of the Left Anterior Descending Artery and Its Diagonal Branch in Dogs and Sheep

2003 ◽  
Vol 26 (4) ◽  
pp. 351-357 ◽  
Author(s):  
W.G. Kim ◽  
Y.C. Shin ◽  
S.W. Hwang ◽  
C. Lee ◽  
C.Y. Na
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery ◽  
Pulmonary Artery ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Suitable Model ◽  
Artery Ligation ◽  
Diagonal Branch ◽  
Left Anterior Descending Artery ◽  
Arterial Blood

We report a comparison of the effects of myocardial infarction in dogs and sheep using sequential ligation of the left anterior descending artery (LAD) and its diagonal branch (DA), with hemodynamic, ultrasonographic and pathological evaluations. Five animals were used in each group. After surgical preparation, the LAD was ligated at a point approximately 40% of the distance from the apex to the base of the heart, and after one hour, the DA was ligated at the same level. Hemodynamic and ultrasonographic measurements were performed preligation, 30 minutes after LAD ligation, and 1 hour after DA ligation. As a control, two animals in each group were used for the simultaneous ligation of the LAD and the DA. Two months after the coronary ligation, the animals were evaluated as previously, and killed for postmortem examination of their hearts. All seven animals in the dog group survived the experimental procedures, while in the sheep group only animals with sequential ligation of the LAD and DA survived. Statistically significant decreases in systemic arterial blood pressure and cardiac output, and an increase in the pulmonary artery capillary wedge pressure (PACWP) were observed one hour after sequential ligation of the LAD and its DA in the sheep, while only systemic arterial pressures decreased in the dog. Ultrasonographic analyses demonstrated variable degrees of anteroseptal dyskinesia and akinesia in all sheep, but in no dogs. Data two months after coronary artery ligation showed significant increases in central venous pressure, pulmonary artery pressure, and PACWP in the sheep, but not in the dog. Left ventricular end-diastolic dimension and left ventricular end-systolic dimension in ultrasonographic studies were also increased only in the sheep. Pathologically, the well-demarcated thin-walled transmural anteroseptal infarcts with chamber enlargement were clearly seen in all specimens of sheep, and only-mild-to-moderate chamber enlargements with endocardial fibrosis were observed in the dog hearts. In conclusion, this study confirms that the dog is not a suitable model for myocardial infarction with failure by coronary artery ligation despite negligent operative mortality, when compared directly with an ovine model.

scholarly journals Circulating Long Noncoding RNA HOTAIR is an Essential Mediator of Acute Myocardial Infarction

2017 ◽  
Vol 44 (4) ◽  
pp. 1497-1508 ◽  
Author(s):  
Lu Gao ◽  
Yuan Liu ◽  
Sen Guo ◽  
Rui Yao ◽  
Leiming Wu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Coronary Artery ◽  
Neonatal Rat ◽  
Luciferase Reporter ◽  
Coronary Artery Ligation ◽  
Healthy Controls ◽  
Artery Ligation ◽  
Cultured Cardiomyocytes

Background/Aims: Acute myocardial infarction (AMI) is one of the leading causes of death in the world. However, specific diagnostic biomarkers have not been fully determined, and candidate regulatory targets for AMI have not been identified to date. Long noncoding RNAs (lncRNAs) are a class of RNA molecules that have diverse regulatory functions during embryonic development, normal life, and disease in higher organisms. However, research on the role of lncRNAs in cardiovascular diseases, particularly AMI, is still in its infancy. HOX antisense intergenic RNA (HOTAIR), a 2.2 kb lncRNA, was initially described as a modulator of HOX gene expression. Recent studies have illustrated the important role of HOTAIR in cancer progression, but few studies have reported its function in cardiac disease, including AMI. In the current study, we aimed to detect the expression of HOTAIR during AMI and to explore its function in hypoxia-induced cardiomyocyte injury in neonatal cardiomyocytes. Methods: In 50 consecutively enrolled AMI patients, we examined the serum expression levels of HOTAIR and analysed its correlation with cardiac troponin I (cTnI) expression. Another 50 age- and sex-matched subjects served as healthy controls. Next, the HOTAIR expression was detected in the serum from C57BL/6J mice subjected to coronary artery ligation and in neonatal rat cardiomyocytes induced by hypoxia. Cultured cardiomyocytes apoptosis were measured by terminal deoxynucleotide transferase dUTP nick end labelling (TUNEL) staining. A search for miRNAs that had complementary base paring with HOTAIR was performed utilizing an online software program, and the interaction between miR-1 and HOTAIR was examined using a luciferase reporter assay. Results: Our study revealed that HOTAIR expression was significantly decreased in the serum of AMI patients compared with that of the healthy controls. Similarly, we observed that HOTAIR was downregulated in the serum of mice subjected to coronary artery ligation and in cultured cardiomyocytes exposed to hypoxia. Furthermore, we observed that the adenovirus vector-driven overexpression of HOTAIR dramatically limited hypoxia-induced myocyte apoptosis, whereas knockdown HOTAIR by AdshHOTAIR (adenoviral short hairpin HOTAIR) exhibited the opposite phenotype. Mechanistically, we discovered that the cardioprotective function of HOTAIR is partly based on the negative regulation of miR-1. Conclusions: Taken together, the results of our study suggest that HOTAIR is a protective factor for cardiomyocytes and that the plasma concentration of HOTAIR may serve as a biomarker for human AMI diagnosis.

scholarly journals Progression of heart failure after myocardial infarction in the rat

2001 ◽  
Vol 281 (5) ◽  
pp. R1734-R1745 ◽  
Author(s):  
J. Francis ◽  
R. M. Weiss ◽  
S. G. Wei ◽  
A. K. Johnson ◽  
R. B. Felder
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Systolic Function ◽  
Left Ventricular Remodeling ◽  
Plasma Renin ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation

This study examined the early neurohumoral events in the progression of congestive heart failure (CHF) after myocardial infarction (MI) in rats. Immediately after MI was induced by coronary artery ligation, rats had severely depressed left ventricular systolic function and increased left ventricular end-diastolic volume (LVEDV). Both left ventricular function and the neurohumoral indicators of CHF underwent dynamic changes over the next 6 wk. LVEDV increased continuously over the study interval, whereas left ventricular stroke volume increased but reached a plateau at 4 wk. Plasma renin activity (PRA), arginine vasopressin, and atrial natriuretic factor all increased, but with differing time courses. PRA declined to a lower steady-state level by 4 wk. Six to 8 wk after MI, CHF rats had enhanced renal sympathetic nerve activity and blunted baroreflex regulation. These findings demonstrate that the early course of heart failure is characterized not by a simple “switching on” of neurohumoral drive, but rather by dynamic fluctuations in neurohumoral regulation that are linked to the process of left ventricular remodeling.

Bradykinin metabolism in rat hearts with left-ventricular hypertrophy following myocardial infarction

2003 ◽  
Vol 81 (7) ◽  
pp. 740-746 ◽  
Author(s):  
Marie-Josée Dumoulin ◽  
Albert Adam ◽  
Jean-Lucien Rouleau ◽  
Hugues Gosselin ◽  
Daniel Lamontagne
Keyword(s):  
Myocardial Infarction ◽  
Left Ventricular Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Neutral Endopeptidase ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Relative Contribution ◽  
The Difference ◽  
Level Of Significance

The aim of the present study was to assess the contribution of angiotensin I converting enzyme (ACE) and neutral endopeptidase (NEP) in the coronary degradation of bradykinin (BK) after left-ventricular hypertrophy following myocardial infarction (MI) in rats. Myocardial infarction was induced by left descendant coronary artery ligation, and the contribution of ACE and NEP in the degradation of exogenous BK after a single passage through the coronary bed was assessed at 2, 5, and 36 days post-MI. BK degradation rate (Vmax/Km) was found to be significantly lower in hearts at 36 days (3.30 ± 0.28 min–1) compared with 2 days (4.39 ± 0.32 min–1) for noninfarcted hearts, but this reduction was just above the statistical level of significance for post-MI hearts. In infarcted hearts, Vmax/Km was increased significantly 5 days post-MI (4.91 ± 0.28 min–1) compared with the 2 and 36 day-groups (3.43 ± 0.20 and 2.78 ± 0.16 min–1, respectively). The difference between noninfarcted and MI was significant only 2 days post-MI. Treatment with the vasopeptidase inhibitor, omapatrilat, showed that the relative contribution of ACE and NEP combined increased over time in infarcted hearts and became significantly higher 36 versus 2 days post-MI. Finally, the treatment with an ACE inhibitor (enalaprilat) and a NEP inhibitor (retrothiorphan) in the 36-day infarcted and noninfarcted hearts showed that the relative contribution of ACE in infarcted hearts was comparable with that of noninfarcted hearts, whereas the relative contribution of NEP was increased significantly in infarcted hearts. In conclusion, experimental MI in rats induces complex changes in the metabolism of exogenous BK. The changes resulted in an increased relative contribution of NEP 36 days after infarction.Key words: bradykinin, ACE, NEP, myocardial infarction.

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.

Abstract 18592: Anti-arrhythmic Effect of a Novel Rycal, S44121 / Arm036, in a Post-myocardial Infarction Mouse Model of Heart Failure

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jerome Thireau ◽  
Charlotte Farah ◽  
Muriel Bouly ◽  
Jerome Roussel ◽  
Alain Lacampagne ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Mouse Model ◽  
Ryanodine Receptors ◽  
Left Ventricular ◽  
Cardiac Contraction ◽  
Post Myocardial Infarction ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Introduction: Targeting leaky cardiac ryanodine receptors (RyR2) to prevent diastolic Ca2+ release from the sarcoplasmic reticulum (SR) is a promising pharmacological approach, to rescue the impaired cardiac contraction and prevent Ca2+-dependent arrhythmias in heart failure (HF) and disease. Hypothesis: Based on prior work from the Marks group, the Rycal S44121 (also known as ARM036) is an experimental small molecule stabilizer of RyR. We investigated the effects of S44121 in a post-myocardial infarction (PMI) mouse model of HF. Methods and results: Mice were randomly assigned to 3 groups: Sham, PMI (subjected to left coronary artery ligation), and PMI-S (treated for 3 weeks with S44121 by subcutaneous osmotic pumps on day 7 post-MI, 10 mg/kg/day). Intracellular Ca2+ was measured on single left ventricular myocytes. PMI mice exhibited a 4-fold increase in the frequency of spontaneous Ca2+ release events, Ca2+ sparks, as measured in quiescent cells using the fluorescent Ca2+ indicator Fluo-4. PMI mice also exhibited higher global diastolic Ca2+, measured with the ratiometric fluorescent probe, Indo-1 AM, and increased the occurrence of ectopic diastolic Ca2+ waves. Acute application of S44121 (10 μM for 15 min) reduced Ca2+ sparks frequency. Chronic treatment of mice with S44121 also normalized the frequency of Ca2+ sparks and of ectopic Ca2+ waves, and corrected diastolic cellular Ca2+ overload. Effects were maximal at 20 mg/kg/day. Furthermore, treatment with S44121 abolished Ca2+ waves promoted by β-adrenergic challenge (acute application of isoproterenol, 10 nM). The potential anti-arrhythmic benefit of S44121 was assessed in vivo using telemetric surface electrocardiograms. S44121 had no effect on ECG intervals and did not alter the heart rate. However, anti-arrhythmic effects were confirmed by observation of a dose-dependent reduction of spontaneous ventricular extrasystoles and ventricular tachycardia. Near maximum benefits were observed at 10 mg/kg/day, both in basal conditions or following a challenge with acute treatment of isoproterenol (0.5 mg/kg, dosed ip). Conclusion: In mice with post-ischemic HF, treatment with S44121 prevented the abnormal diastolic SR Ca2+ leak and ectopic Ca2+ waves, and reduced ventricular arrhythmias.

Abstract 15058: Disruption of Extracellular Cytotoxic Chromatin by Acute DNase1 Administration Improves Left Ventricular Remodeling after Myocardial Infarction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Benjamin Vogel ◽  
Hisahito Shinagawa ◽  
Ullrich Hofmann ◽  
Georg Ertl ◽  
Stefan Frantz
Keyword(s):  
Myocardial Infarction ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular ◽  
Pcr Analysis ◽  
Coronary Artery Ligation ◽  
Protective Effects ◽  
Artery Ligation ◽  
High Concentrations

Rationale: Myocardial infarction (MI) leads to necrosis of multinucleated and polyploid myocytes. This causes uncontrolled release of cellular content like chromatin to the infarct area. Chromatin is mainly comprised of histones which are essential for controlling and packing of DNA but paradoxically are also known to be cytotoxic. This makes free chromatin a toxic DNA polymer creating local high concentrations of hazardous histones. Objective: We hypothesized that chromatin from necrotic cells accumulates in ischemic myocardium, creates local high concentrations of cytotoxic histones, and thereby potentiates ischemic damage to the heart after MI. The endonuclease DNase1 is capable of dispersing extracellular chromatin through linker DNA digestion and could decrease local histone concentrations and cytotoxicity. Methods and Results: After permanent coronary artery ligation in mice we found extracellular histones accumulated within the infarcted myocardium. Histone cytotoxicity towards isolated myocytes was confirmed in vitro. To reduce histone related cytotoxicity in vivo DNase1 was injected within the first 6 hours after induction of MI. DNase1 accumulated in the infarcted region of the heart, effectively disrupted extracellular cytotoxic chromatin and thereby reduced high local histone concentration. Animals acutely treated with DNase1 revealed significantly improved left ventricular remodeling as measured by serial echocardiography up to 28 days after MI (e.g. NaCl vs DNase1, papillary end diastolic area [mm 2 ]: 23.26 ± 2.06 vs 18.90 ± 1.24, n=9 vs 10, p<0,05). Treatment did not influence mortality, infarct size or inflammatory parameters as determined by neutrophil infiltration and RTQ-PCR analysis of characteristic cytokines. However improved myocyte survival was discovered within the infarct region which might account for the protective effects in DNase1 treated animals (NaCl vs DNase1: 3.0 ± 0.7% vs 8.3 ± 2.3%; p<0.05; n=7 vs 8). Conclusions: Targeting extracellular cytotoxic chromatin within the infarcted heart by DNase1 is a promising approach to preserve myocytes from histone induced cell death and to conserve left ventricular function after MI. The efficacy of other chromatin degrading agents is now under investigation.

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