Experimental Myocardial Infarction Research Articles

Mineralocorticoid Receptor Blocker Prevents Mineralocorticoid Receptor-Mediated Inflammation by Modulating Transcriptional Activity of Mineralocorticoid Receptor-p65-Signal Transducer and Activator of Transcription 3 Complex.

Mineralocorticoid receptor (MR) induces cardiac inflammation cooperatively with nuclear factor-κB and signal transducer and activator of transcription 3 (STAT3); MR blockers exert anti-inflammatory effects. However, the underlying mechanism remains unclear. We investigated the anti-inflammatory effect of esaxerenone, a novel MR blocker, in experimental myocardial infarction (MI) and its underlying mechanisms. Male C57BL/6J mice subjected to ligation of the left anterior descending artery were randomly assigned to either the vehicle or esaxerenone group. Esaxerenone was provided with a regular chow diet. The mice were euthanizedat either 4 or 15 days after MI. Cardiac function, fibrosis, and inflammation were evaluated. Esaxerenone significantly improved cardiac function and attenuated cardiac fibrosis at 15 days after MI independently of its antihypertensive effect. Inflammatory cell infiltration, inflammatory-related gene expression, and elevated serum interleukin-6 levels at 4 days after MI were significantly attenuated by esaxerenone. Invitro experiments using mouse macrophage-like cell line RAW264.7 cells demonstrated that esaxerenone- and spironolactone-attenuated lipopolysaccharide-induced interleukin-6 expression without altering the posttranslational modification and nuclear translocation of p65 and STAT3. Immunoprecipitation assays revealed that MR interacted with both p65 and STAT3 and enhanced the p65-STAT3 interaction, leading to a subsequent increase in interleukin-6 promoter activity, which was reversed by esaxerenone. Esaxerenone ameliorated postinfarct remodeling in experimental MI through its anti-inflammatory properties exerted by modulating the transcriptional activity of the MR-p65-STAT3 complex. These results suggest that the MR-p65-STAT3 complex can be a novel therapeutic target for treating MI.

DNA-sensing inflammasomes cause recurrent atherosclerotic stroke

The risk of early recurrent events after stroke remains high despite currently established secondary prevention strategies1. Risk is particularly high in patients with atherosclerosis, with more than 10% of patients experiencing early recurrent events1,2. However, despite the enormous medical burden of this clinical phenomenon, the underlying mechanisms leading to increased vascular risk and recurrent stroke are largely unknown. Here, using a novel mouse model of stroke-induced recurrent ischaemia, we show that stroke leads to activation of the AIM2 inflammasome in vulnerable atherosclerotic plaques via an increase of circulating cell-free DNA. Enhanced plaque inflammation post-stroke results in plaque destabilization and atherothrombosis, finally leading to arterioarterial embolism and recurrent stroke within days after the index stroke. We confirm key steps of plaque destabilization also after experimental myocardial infarction and in carotid artery plaque samples from patients with acute stroke. Rapid neutrophil NETosis was identified as the main source of cell-free DNA after stroke and NET–DNA as the causative agent leading to AIM2 inflammasome activation. Neutralization of cell-free DNA by DNase treatment or inhibition of inflammasome activation reduced the rate of stroke recurrence after experimental stroke. Our findings present an explanation for the high recurrence rate after incident ischaemic events in patients with atherosclerosis. The detailed mechanisms uncovered here provide clinically uncharted therapeutic targets for which we show high efficacy to prevent recurrent events. Targeting DNA-mediated inflammasome activation after remote tissue injury represents a promising avenue for further clinical development in the prevention of early recurrent events.

Effect of Intramyocardial Administration of Baculovirus Encoding the Transcription Factor Tbx20 in Sheep With Experimental Acute Myocardial Infarction.

Gene therapy has been proposed as a strategy to induce cardiac regeneration following acute myocardial infarction (AMI). Given that Tbx20, a transcription factor of the T-box subfamily, stimulates cell proliferation and angiogenesis, we designed a baculovirus overexpressing Tbx20 (Bv-Tbx20) and evaluated its effects in cultured cardiomyocytes and in an ovine model of AMI. Cell proliferation and angiogenesis were measured in cardiomyocytes transduced with Bv-Tbx20 or Bv-Null (control). Subsequently, in sheep with AMI, Bv-Tbx20 or Bv-Null was injected in the infarct border. Cardiomyocyte cell cycle activity, angioarteriogenesis, left ventricular function, and infarct size were assessed. Cardiomyocytes transduced with BvTbx20 increased cell proliferation, cell cycle regulatory and angiogenic gene expression, and tubulogenesis. At 7 days posttreatment, sheep treated with Bv-Tbx20 showed increased Tbx20, promitotic and angiogenic gene expression, decreased levels of P21, increased Ki67- (17.09±5.73 versus 7.77±7.24 cardiomyocytes/mm2, P<0.05) and PHH3 (phospho-histone H3)-labeled cardiomyocytes (10.10±3.51 versus 5.23±2.87 cardiomyocytes/mm2, P<0.05), and increased capillary (2302.68±353.58 versus 1694.52±211.36 capillaries/mm2, P<0.001) and arteriolar (146.95±53.14 versus 84.06±16.84 arterioles/mm2, P<0.05) densities. At 30 days, Bv-Tbx20 decreased infarct size (9.89±1.92% versus 12.62±1.33%, P<0.05) and slightly improved left ventricular function. Baculoviral gene transfer-mediated Tbx20 overexpression exerted angiogenic and cardiomyogenic effects invitro. In sheep with AMI, Bv-Tbx20 induced angioarteriogenesis, cardiomyocyte cell cycle activity, infarct size limitation, and a slight recovery of left ventricular function, suggesting that Bv-Tbx20 gene therapy may contribute to cardiac regeneration following AMI.

Targeting calpain-2-mediated junctophilin-2 cleavage delays heart failure progression following myocardial infarction

Coronary heart disease (CHD) is a prevalent cardiac disease that causes over 370,000 deaths annually in the USA. In CHD, occlusion of a coronary artery causes ischemia of the cardiac muscle, which results in myocardial infarction (MI). Junctophilin-2 (JPH2) is a membrane protein that ensures efficient calcium handling and proper excitation-contraction coupling. Studies have identified loss of JPH2 due to calpain-mediated proteolysis as a key pathogenic event in ischemia-induced heart failure (HF). Our findings show that calpain-2-mediated JPH2 cleavage yields increased levels of a C-terminal cleaved peptide (JPH2-CTP) in patients with ischemic cardiomyopathy and mice with experimental MI. We created a novel knock-in mouse model by removing residues 479-SPAGTPPQ-486 to prevent calpain-2-mediated cleavage at this site. Functional and molecular assessment of cardiac function post-MI in cleavage site deletion (CSD) mice showed preserved cardiac contractility and reduced dilation, reduced JPH2-CTP levels, attenuated adverse remodeling, improved T-tubular structure, and normalized SR Ca2+-handling. Adenovirus mediated calpain-2 knockdown in mice exhibited similar findings. Pulldown of CTP followed by proteomic analysis revealed valosin-containing protein (VCP) and BAG family molecular chaperone regulator 3 (BAG3) as novel binding partners of JPH2. Together, our findings suggest that blocking calpain-2-mediated JPH2 cleavage may be a promising new strategy for delaying the development of HF following MI.

Cardioprotective effects of native herb-derived cardiac tonic on infarct size in a mouse model of experimental myocardial infarction

Cardiac remodeling is a significant issue involving molecular, cellular, and interstitial changes that affect the size, mass, integrity, and function of the heart following a myocardial infarction (MI). We hypothesized that therapy with mixed herbal extracts has a protective effect in mouse models of MI. The underlying mechanisms are thought to be protective against left ventricular (LV) remodeling through reduced collagen deposition. We therefore studied the effects of mixed herbal extracts commonly used in various ways in the belief that they have beneficial effects on cardiac disease. MI was induced by left anterior descending (LAD) coronary artery ligation in switch albino mice. Ethanol extracts of herbs Arjuna bark, oleander leaves, ginseng root, garlic, cardamom seeds and oregano leaves were prepared by ethanol extraction and rotary evaporation technique of dried herbs and then mixed the extracts to make a therapeutic cocktail. The mixture is then administered orally by lavage for 28 days. At the end of 28 days cardiac tissues were harvested and stored for histopathology analysis and assessment of SOD levels. Survival curve data over a period of 28 days showed significant (P&lt;0.05) differences between groups and mortality was reduced in the herbal extract treated group. Heart mass especially ventricular and atrial space and ratio of ​​infarct to total heart area revealed better improvement in treated group compared to untreated group. Histopathological studies showed that the myocardium of the herbal extract treated group had fewer collagen fibers than the non-treated group. SOD activity levels were up-regulated in animals treated with herbal extracts indicating reduction of oxidative stress by herbal extract mixture. Hence, their effects reduce collagen deposition, reduce LV mass and prevent myocardial tissue damage, reduce structural changes and increase survival by their anti-stress effects. Mixed herbal tonic may provide a new therapeutic approach in ischemic cardiomyopathy and ischemic heart failure. Asian Australas. J. Biosci. Biotechnol. 2024, 9(2), 14-23

MiR-214–3p regulates Piezo1, lysyl oxidases and mitochondrial function in human cardiac fibroblasts

Cardiac fibroblasts are pivotal regulators of cardiac homeostasis and are essential in the repair of the heart after myocardial infarction (MI), but their function can also become dysregulated, leading to adverse cardiac remodelling involving both fibrosis and hypertrophy. MicroRNAs (miRNAs) are noncoding RNAs that target mRNAs to prevent their translation, with specific miRNAs showing differential expression and regulation in cardiovascular disease. Here, we show that miR-214–3p is enriched in the fibroblast fraction of the murine heart, and its levels are increased with cardiac remodelling associated with heart failure, or in the acute phase after experimental MI. Tandem mass tagging proteomics and in-silico network analyses were used to explore protein targets regulated by miR-214–3p in cultured human cardiac fibroblasts from multiple donors. Overexpression of miR-214–3p by miRNA mimics resulted in decreased expression and activity of the Piezo1 mechanosensitive cation channel, increased expression of the entire lysyl oxidase (LOX) family of collagen cross-linking enzymes, and decreased expression of an array of mitochondrial proteins, including mitofusin-2 (MFN2), resulting in mitochondrial dysfunction, as measured by citrate synthase and Seahorse mitochondrial respiration assays. Collectively, our data suggest that miR-214–3p is an important regulator of cardiac fibroblast phenotypes and functions key to cardiac remodelling, and that this miRNA represents a potential therapeutic target in cardiovascular disease.

Evaluating the therapeutic effect of vitamin D and nerolidol on lung injury due to experimental myocardial infarction: The potential role of asprosin and spexin

Injury to internal organs caused by myocardial infarction (MI), although often neglected, is a very serious condition which damages internal organs especially the lungs. Changes in microcirculation can begin with acute lung injury and result in severe respiratory failure. The aim of this study was to create new approaches that will explain the pathophysiology and treatment of the disease by examining the therapeutic effects of vitamin D (VITD) and Nerolidol (NRD) on the injuries of the lungs caused by MI, and their relationship with asprosin / spexin proteins. MethodsSix groups of seven experimental animals each were constituted. Control, VITD (only 50 IU/day during the experiment), NRD (only 100 mg/kg/day during the experiment), MI (200 mg/kg isoproterenol was administered to rats as a single dose subcutaneously), MI+VITD (200 mg/kg isoproterenol +50 IU/day) and MI+NRD (200 mg/kg isoproterenol +100 mg/kg/day) were the six (6) groups constituted. Tissues were analyzed using histopathological and immunohistochemical methods, whereas serum samples were analyzed using ELISA method. ResultsThe result of the histopathological study for the MI group showed an observed increase in inflammatory cells, congestion, interalveolar septal thickening, erythrocyteloaded macrophages and fibrosis in the lung tissues. The treatment groups however recorded significant differences with regards to these parameters. In the immunohistochemical analysis, expressions of asprosin and spexin were observed in the smooth muscle structures and interalveolar areas of the vessels and bronchioles of the lung, as well as the bronchiole epithelium. There was no significant difference between the groups in terms of asprosin and spexin expression in the bronchiol epithelium.When immunohistochemical and serum ELISA results were examined, it was observed that asprosin levels increased significantly in the lung tissues of the MI group compared to the control group, decreased significantly in the treatment groups treated with Vitamin D and NRD after MI. While spexin decreased significantly in the MI group compared to the control group, it increased significantly in the MI+VİTD group, but did not change in the MI+NRD group. ConclusionIt was observed that serious injuries occurred in the lungs due to myocardial infarction and that, VITD and NRD treatments had a curative effect on those injuries. It was also observed that Asprosin and Speksin proteins can have effect on mechanisms of both injury and therapy of the lung. Furthermore, the curative effects of VITD are dependent on the expression of asprosin and spexin; whereas the observation indicated that nerolidol could be effective through asprosin-dependent mechanisms and specisin by independent mechanisms.

Novel Fibrillar and Non-Fibrillar Collagens Involved in Fibrotic Scar Formation after Myocardial Infarction.

Following myocardial infarction (MI), adverse remodeling depends on the proper formation of fibrotic scars, composed of type I and III collagen. Our objective was to pinpoint the participation of previously unreported collagens in post-infarction cardiac fibrosis. Gene (qRT-PCR) and protein (immunohistochemistry followed by morphometric analysis) expression of fibrillar (types II and XI) and non-fibrillar (types VIII and XII) collagens were determined in RNA-sequencing data from 92 mice undergoing myocardial ischemia; mice submitted to permanent (non-reperfused MI, n = 8) or transient (reperfused MI, n = 8) coronary occlusion; and eight autopsies from chronic MI patients. In the RNA-sequencing analysis of mice undergoing myocardial ischemia, increased transcriptomic expression of collagen types II, VIII, XI, and XII was reported within the first week, a tendency that persisted 21 days afterwards. In reperfused and non-reperfused experimental MI models, their gene expression was heightened 21 days post-MI induction and positively correlated with infarct size. In chronic MI patients, immunohistochemistry analysis demonstrated their presence in fibrotic scars. Functional analysis indicated that these subunits probably confer tensile strength and ensure the cohesion of interstitial components. Our data reveal that novel collagens are present in the infarcted myocardium. These data could lay the groundwork for unraveling post-MI fibrotic scar composition, which could ultimately influence patient survivorship.

Thioredoxin-2 protects mice against experimental myocardial infarction

Thioredoxin-2 protects mice against experimental myocardial infarction

Differential sex-dependent role of lncRNAs in cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Education and Science Cardiovascular diseases are one of the most prevalent causes of mortality and morbidity worldwide. Structural diseases such as dilated and hypertrophic cardiomyopathy significantly contributed to it. In recent years, several studies have pinpointed the importance of non-coding genome in the pathogenesis of cardiomyopathy. We have previously reported the role of distinct lncRNAs in atrial fibrillation. We now explored the plausible role of these lncRNAs in cardiomyopathy by analyzing their expression in two different mouse mutant models of lamin (LMNA) - LMNAR249W and αMHCCreLMNAFF, a cardiac hypertrophic MyBPC3 mutant model as well as in experimental myocardial infarction mice. Importantly, both LMNA mutant models developed a dilated cardiomyopathy, a condition distinctly observed in males but not in females. Our data demonstrated that Walras, Gm26533, Wallrd, Walaa and Walrad are downregulated in females, but not males. Furthermore, differential deregulation is also observed in MyBPC3 mutant model but not in myocardial infarction. In vitro analyses demonstrated an estrogen-dependent regulation. In addition, expression analyses in distinct cardiovascular cell lines revealed enriched myocardial expression of Walras and Gm26533 while Wallrd and Walaa are preferentially expressed in endocardial cells. These data were further validated by in situ hybridization in embryonic cardiac tissues. Walras overexpression resulted in enhanced expression of two key factors of UPR signaling pathway, i.e. Atf6 and Ire1, while Walras inhibition downregulated them. Upregulation of both UPR factors in Walrasgain-of-function assays is accompanied by increased cardiomyocyte apoptosis. In contrast, Walras inhibition resulted in increased Bcl2 expression and therefore increased cell viability. Mechanistically, Walras directly interacts with calumenin protein, a known protective factor against UPR-associated apoptosis, as demonstrated by pulldown assays. In sum, we demonstrated sex-dependent regulation of distinct lncRNAs in different cardiomyopathic mouse models and at least one of them, i.e. Walras contributes to UPR-associated apoptosis regulation, providing a causative link to the development of distinct cardiomyopathies.

CCR2+ monocytes promote white matter injury and cognitive dysfunction after myocardial infarction

Survivors of myocardial infarction are at increased risk for vascular dementia. Neuroinflammation has been implicated in the pathogenesis of vascular dementia, yet little is known about the cellular and molecular mediators of neuroinflammation after myocardial infarction. Using a mouse model of myocardial infarction coupled with flow cytometric analyses and immunohistochemistry, we discovered increased monocyte abundance in the brain after myocardial infarction, which was associated with increases in brain-resident perivascular macrophages and microglia. Myeloid cell recruitment and activation was also observed in post-mortem brains of humans that died after myocardial infarction. Spatial and single cell transcriptomic profiling of brain-resident myeloid cells after experimental myocardial infarction revealed increased expression of monocyte chemoattractant proteins. In parallel, myocardial infarction increased crosstalk between brain-resident myeloid cells and oligodendrocytes, leading to neuroinflammation, white matter injury, and cognitive dysfunction. Inhibition of monocyte recruitment preserved white matter integrity and cognitive function, linking monocytes to neurodegeneration after myocardial infarction. Together, these preclinical and clinical results demonstrate that monocyte infiltration into the brain after myocardial infarction initiate neuropathological events that lead to vascular dementia.

Recombinant human soluble domain of CD39L3 and ticagrelor: cardioprotective effects in experimental myocardial infarction.

The ecto-nucleoside triphosphate diphosphohydrolases of the CD39 family degrade ATP and ADP into AMP, which is converted into adenosine by the extracellular CD73/ecto-5-nucleotidase. This pathway has been explored in antithrombotic treatments but little in myocardial protection. We have investigated whether the administration of solCD39L3 (AZD3366) confers additional cardioprotection to that of ticagrelor alone in a pre-clinical model of myocardial infarction (MI). Ticagrelor-treated pigs underwent balloon-induced MI (90 min) and, before reperfusion, received intravenously either vehicle, 1 mg/kg AZD3366 or 3 mg/kg AZD3366. All animals received ticagrelor twice daily for 42 days. A non-treated MI group was run as a control. Serial cardiac magnetic resonance (baseline, Day 3 and Day 42 post-MI), light transmittance aggregometry, bleeding time, and histological and molecular analyses were performed. Ticagrelor reduced oedema formation and infarct size at Day 3 post-MI vs. controls. A 3 mg/kg AZD3366 provided an additional 45% reduction in oedema and infarct size compared with ticagrelor and a 70% reduction vs. controls (P < .05). At Day 42, infarct size declined in all ticagrelor-administered pigs, particularly in 3 mg/kg AZD3366-treated pigs (P < .05). Left ventricular ejection fraction was diminished at Day 3 in placebo pigs and worsened at Day 42, whereas it remained unaltered in ticagrelor ± AZD3366-administered animals. Pigs administered with 3 mg/kg AZD3366 displayed higher left ventricular ejection fraction upon dobutamine stress at Day 3 and minimal dysfunctional segmental contraction at Day 42 (χ2P < .05 vs. all). Cardiac and systemic molecular readouts supported these benefits. Interestingly, AZD3366 abolished ADP-induced light transmittance aggregometry without affecting bleeding time. Infusion of AZD3366 on top of ticagrelor leads to enhanced cardioprotection compared with ticagrelor alone.

Role of CD4+ T-cells for regulating splenic myelopoiesis and monocyte differentiation after experimental myocardial infarction

Myocardial infarction (MI) induces the generation of proinflammatory Ly6Chigh monocytes in the spleen and the recruitment of these cells to the myocardium. CD4+ Foxp3+ CD25+ T-cells (Tregs) promote the healing process after myocardial infarction by engendering a pro-healing differentiation state in myocardial monocyte-derived macrophages. We aimed to study the effects of CD4+ T-cells on splenic myelopoiesis and monocyte differentiation. We instigated MI in mice and found that MI-induced splenic myelopoiesis is abrogated in CD4+ T-cell deficient animals. Conventional CD4+ T-cells promoted myelopoiesis in vitro by cell–cell-contact and paracrine mechanisms, including interferon-gamma (IFN-γ) signalling. Depletion of regulatory T-cells enhanced myelopoiesis in vivo, as evidenced by increases in progenitor cell numbers and proliferative activity in the spleen 5 days after MI. The frequency of CD4+ T-cells-producing factors that promote myelopoiesis increased within the spleen of Treg-depleted mice. Moreover, depletion of Tregs caused a proinflammatory bias in splenic Ly6Chigh monocytes, which showed predominantly upregulated expression of IFN-γ responsive genes after MI. Our results indicate that conventional CD4+ T-cells promote and Tregs attenuate splenic myelopoiesis and proinflammatory differentiation of monocytes.

Cathelicidin Antimicrobial Peptide Levels in Atherosclerosis and Myocardial Infarction in Mice and Human.

Obesity represents a worldwide health challenge, and the condition is accompanied by elevated risk of cardiovascular diseases caused by metabolic dysfunction and proinflammatory adipokines. Among those, the immune-modulatory cathelicidin antimicrobial peptide (human: CAMP; murine: CRAMP) might contribute to the interaction of the innate immune system and metabolism in these settings. We investigated systemic CAMP/CRAMP levels in experimental murine models of atherosclerosis, myocardial infarction and cardiovascular patients. Atherosclerosis was induced in low-density lipoprotein receptor-deficient (Ldlr-/-) mice by high-fat diet (HFD). C57BL/6J wild-type mice were subjected to myocardial infarction by permanent or transient left anterior descending (LAD)-ligation. Cramp gene expression in murine organs and tissues was investigated via real-time PCR. Blood samples of 234 adult individuals with or without coronary artery disease (CAD) were collected. Human and murine CAMP/CRAMP serum levels were quantified by ELISA. Atherosclerotic mice exhibited significantly increased CRAMP serum levels and induced Cramp gene expression in the spleen and liver, whereas experimental myocardial infarction substantially decreased CRAMP serum levels. Human CAMP serum quantities were not significantly affected by CAD while being correlated with leukocytes and pro-inflammatory cytokines. Our data show an influence of cathelicidin in experimental atherosclerosis, myocardial infarction, as well as in patients with CAD. Further studies are needed to elucidate the pathophysiological mechanism.

Cardioprotective effects of p-coumaric acid on tachycardia, inflammation, ion pump dysfunction, and electrolyte imbalance in isoproterenol-induced experimental myocardial infarction.

Cardiovascular diseases cause a large number of deaths throughout the world. No research was conducted earlier on p-coumaric acid's effect on tachycardia, inflammation, ion pump dysfunction, and electrolyte imbalance. Hence, we appraised the above-said parameters in isoproterenol-induced myocardial infarcted rats. This investigation included 24 male albino Wistar rats in 4 groups. Normal control Group 1, p-coumaric acid (8 mg/kg body weight) alone treated Group 2, Isoproterenol (100 mg/kg body weight) induced myocardial infarcted Group 3, p-coumaric acid (8 mg/kg body weight) pretreated isoproterenol (100 mg/kg body weight) induced Group 4. After 1 day of the last dose of isoproterenol injection (day 10), rats were killed and blood and heart were taken and inflammatory markers, lipid peroxidation, nonenzymatic antioxidants, ion pumps, and electrolytes were measured. The heart rate, serum cardiac troponin-T, serum/plasma inflammatory markers, and heart proinflammatory cytokines were raised in isoproterenol-induced rats. Isoproterenol also enhanced plasma lipid peroxidation, lessened plasma nonenzymatic antioxidants, and altered heart ion pumps and serum and heart electrolytes. In this study, p-coumaric acid pretreatment orally for 7 days to isoproterenol-induced myocardial infarcted rats prevented changes in the above-cited parameters. p-Coumaric acid's anti-tachycardial, anti-inflammatory, anti-ion pump dysfunction and anti-electrolyte imbalance properties are the mechanisms for these cardioprotective effects.

Thioredoxin 2 protects mice against experimental myocardial infarction

Graphical abstract Experimental Myocardial infarction (MI) using ligation procedure induces cardiac dysfunction, high level of ROS, inflammation, apoptosis, fibrosis and cardiomyocyte (CM) loss. AAV overexpressing human Trx-2, specifically in CM mitochondria improves mouse cardiac function, reduces the size of cardiac infarct, increases the expression of cardiac anti-inflammatory markers, reduces apoptosis and oxidative stress. However, it does not increase CM proliferation. Abstract Introduction and objective Myocardial infarction (MI), which in general results from complications of atherosclerosis, is characterized by high inflammation and cardiomyocytes (CMs) apoptosis and by major loss of CMs. Regeneration of these lost CMs represents a major challenge for MI therapy. The increase of mitochondrial reactive oxygen species (ROS) is involved in cell cycle arrest which can be restarted by hypoxia or in the presence of ROS scavengers. Among ROS scavengers, mitochondrial thioredoxin 2 (Trx-2), an important antioxidant protein, could play a role in the CMs renewal. Method In this study, we investigated the effect of Trx-2 on mouse heart after an experimental MI. Results Trx-2 improves mouse cardiac function, reduces cardiac infarction size and increases the expression of cardiac anti-inflammatory markers. In addition, it reduces apoptosis and oxidative stress in heart tissue of mice after MI but it does not increase CM proliferation in cell culture or in heart tissue. Conclusion Mitochondrial Trx-2 effectively protects against heart infarction, likely via the reduction of oxidative stress, inflammation and apoptosis but not through CM renewal. Significance statement The current study unveils the complexities of MI and highlights mitochondrial Trx-2 role. Post-MI, marked by inflammation, CM apoptosis and significant CM loss. Trx-2 emerges as a vital protector. Its intervention improves mouse cardiac function, reduces infarction size and fosters an anti-inflammatory environment. By uncovering these mechanisms, the study suggests potential therapeutic strategies for oxidative stress, inflammation and apoptosis in MI, positioning Trx-2 as a promising candidate for future cardiac interventions.

Macrophage mediators and mechanisms in cardiovascular disease.

Macrophages are major players in myocardial infarction (MI) and atherosclerosis, two major cardiovascular diseases (CVD). Atherosclerosis is caused by the buildup of cholesterol-rich lipoproteins in blood vessels, causing inflammation, vascular injury, and plaque formation. Plaque rupture or erosion can cause thrombus formation resulting in inadequate blood flow to the heart muscle and MI. Inflammation, particularly driven by macrophages, plays a central role in both atherosclerosis and MI. Recent integrative approaches of single-cell analysis-based classifications in both murine and human atherosclerosis as well as experimental MI showed overlap in origin, diversity, and function of macrophages in the aorta and the heart. We here discuss differences and communalities between macrophages in the heart and aorta at steady state and in atherosclerosis or upon MI. We focus on markers, mediators, and functional states of macrophage subpopulations. Recent trials testing anti-inflammatory agents show a major benefit in reducing the inflammatory burden of CVD patients, but highlight a necessity for a broader understanding of immune cell ontogeny and heterogeneity in CVD. The novel insights into macrophage biology in CVD represent exciting opportunities for the development of novel treatment strategies against CVD.

Peracute Myocardial Infarction: Features of the Influence of α2-Adrenoreceptor Stimulation on the Isolated Heart.

We performed a comparative analysis of the effect of α2-adrenoreceptor stimulation on the performance of Langendorff-isolated heart from rats with experimental myocardial infarction in the acute stage and sham-operated animals (control). In animals with peracute myocardial infarction, different agonist concentrations (clonidine, 10-6 and 10-9 M) produced a multidirectional effect on the left-ventricular developed pressure and speed and time parameters of heart contractility. In control rats, both concentrations of the agonist added to the perfused solution reduced contraction force. Clonidine in a concentration of 10-6 M reduced HR in both groups and in a concentration of 10-9 M, it decreased HR in control rats and caused multidirectional changes in rats with myocardial infarction. The coronary flow decreased in all series of experiments.

The Role of Arterial Elasticity in Determining the Degree of Chronic Heart Failure in Myocardial Infarction.

Aim To study the left ventricular (LV) contractile and pumping function during the recovery phase following ligation of the anterior descending coronary artery (CA).Material and methods Cardiodynamic parameters were studied in Wistar rats 2-4 weeks after experimental myocardial infarction (MI). MI was induced by ligation of the anterior descending CA under zoletil anesthesia. LV catheterization was performed with a standard FTH-1912B-8018 PV catheter inserted into the LV through the right carotid artery.Results After the induction of MI, the mortality rate of animals was 50%. Survived animals developed significant LV dilatation and a decrease in ejection fraction (EF) by an average of 31%. However, major indexes of the pumping function, including minute volume, heart work, and maximum ejection velocity, were within a normal range whereas the maximum filling velocity was almost doubled. Approximately 50% of hearts with dilated LV had normal EF, delayed relaxation, and increased LV diastolic pressure, which qualified this group as a diastolic dysfunction group. The systolic dysfunction group with EF less than 50% of normal had similar values of myocardial contractility and relaxation but differed from the diastolic dysfunction group in more than 50% reduced maximum LV ejection velocity and 1.7 times increased elasticity of the arterial wall. A close inverse correlation was found between these values (r= -0.91).Conclusion The study results showed that, with a similar myocardial contractile function, the cardiac pumping function is determined by the elasticity of the aortic wall. Therefore, restriction of reactive fibrosis during MI is an important task of modern cardiology.

Thioredoxin-1 and its mimetic peptide improve systolic cardiac function and remodeling after myocardial infarction.

Myocardial infarction (MI) is characterized by a significant loss of cardiomyocytes (CMs), and it is suggested that reactive oxygen species (ROS) are involved in cell cycle arrest, leading to impaired CM renewal. Thioredoxin-1 (Trx-1) scavenges ROS and may play a role in restoring CM renewal. However, the truncated form of Trx-1, Trx-80, can compromise its efficacy by exerting antagonistic effects. Therefore, a Trx-1 mimetic peptide called CB3 was tested as an alternative way to restore CMs. This study aimed to investigate the effects of Trx-1, Trx-80, and CB3 on mice with experimental MI and study the underlying mechanism of CB3 on CMs. Mouse cardiac parameters were quantified by echocardiography, and infarction size and fibrosis determined using Trichrome and Picro-Sirius Red staining. The study found that Trx-1 and CB3 improved mouse cardiac function, reduced the size of cardiac infarct and fibrosis, and decreased the expression of cardiac inflammatory markers. Furthermore, CB3 polarized macrophages into M2 phenotype, reduced apoptosis and oxidative stress after MI, and increased CM proliferation in cell culture and invivo. CB3 effectively protected against myocardial infarction and could represent a new class of compounds for treating MI.