Important Role In Myocardial Infarction Research Articles

Analysis of the mechanism of liquiritigenin in promoting cardiomyocyte regeneration based on miRNA-34b-TIA-1-SG molecular network-mediated autophagy

This study aims to clarify that miRNA-34b affects the autophagy through regulating TIA-1-SG and explore the role of miRNA-34b-TIA-1-SG molecular network-mediated autophagy in cardiomyocyte regeneration. 32 patients with autophagy injury caused by myocardial ischemia perfusion admitted to the hospital were included and 32 healthy controls were enrolled at the same time. ELISA was used to detect miRNA-34b level. Cardiomyocytes were isolated and cultured by adherence method and the relationship between miRNA-34b and TIA-1-SG was analyzed by dual-luciferase gene reporter assay. The correlation between myocardial autophagy and liquiritigenin treatment was assessed along with qRT-PCR analysis of the changes of genes (TIA-1, SG, ULK1, OsATG7, FAM176A, Beclin 1). miRNA-34b expression in 32 patients with myocardial autophagy injury was higher than normal group. miRNA-34b binds to the 3′-UTR of TIA-1 and transfection of miRNA-34b inhibitor increased the luciferase activity, which was not affected in pMIR-TIA-1-mut group, confirming the relationship between miRNA-34b and TIA-1. The addition of liquiritigenin can promote the reduction of expression of myocardial autophagy injury-related genes. In the absence of liquiritigenin, the expression of genes related to myocardial autophagy injury increased significantly. Autophagy imbalance plays an important role in myocardial infarction, which participates in myocardial infarction. miRNA-34b can target and regulate TIA-1 gene, promote myocardial infarction repair, and inhibit the state of autophagy by regulating autophagy-related gene TIA-1. Liquiritigenin regulates autophagy imbalance in myocardial infarction to delay myocardial remodeling and improve prognosis.

Gasdermin D-mediated pyroptosis in myocardial ischemia and reperfusion injury: Cumulative evidence for future cardioprotective strategies

Cardiomyocyte death is one of the major mechanisms contributing to the development of myocardial infarction (MI) and myocardial ischemia/reperfusion (MI/R) injury. Due to the limited regenerative ability of cardiomyocytes, understanding the mechanisms of cardiomyocyte death is necessary. Pyroptosis, one of the regulated programmed cell death pathways, has recently been shown to play important roles in MI and MI/R injury. Pyroptosis is activated by damage-associated molecular patterns (DAMPs) that are released from damaged myocardial cells and activate the formation of an apoptosis-associated speck-like protein containing a CARD (ASC) interacting with NACHT, LRR, and PYD domains-containing protein 3 (NLRP3), resulting in caspase-1 cleavage which promotes the activation of Gasdermin D (GSDMD). This pathway is known as the canonical pathway. GSDMD has also been shown to be activated in a non-canonical pathway during MI and MI/R injury via caspase-4/5/11. Suppression of GSDMD has been shown to provide cardioprotection against MI and MI/R injury. Although the effects of MI or MI/R injury on pyroptosis have previously been discussed, knowledge concerning the roles of GSDMD in these settings remains limited. In this review, the evidence from invitro, invivo, and clinical studies focusing on cardiac GSDMD activation during MI and MI/R injury is comprehensively summarized and discussed. Implications from this review will help pave the way for a new therapeutic target in ischemic heart disease.

Abstract 10754: AMPKγ2 Deficiency Exacerbates Macrophage Recruitment and Inflammation Post-MI via Promoting YY1-CXCL16-CXCR6 Axis

Background: Acute myocardial infarction (MI) has got revolutionized therapeutic strategy by applying timely reperfusion therapy in a particular increase of primary percutaneous coronary intervention. Despite this cardiac remodeling following MI are very common with high mortality. A previous study claimed that AMPK played a pivotal role in intracellular adaptation to energy stress during myocardial ischemia. However, whether AMPKγ2 subunit played an important role in MI remains poorly defined. Hypothesis: We assessed the hypothesis that AMPKγ2 played an important role in regulating MI. Methods: AMPKγ2 level in monocytes of myocardial infarction patients was tested by ELISA. Ligation of left anterior descending branch (LAD) surgery was conducted to establish MI model. Lyz2-cre AMPKγ2 and AAV carrying F4/80 promoter for macrophage-specific overexpression AMPKγ2 mice were employed to investigate the role of AMPKγ2 in macrophages derived from MI. Results: AMPKγ2 was relatively highly expressed in the spleen and macrophage. Lyz2-cre AMPKγ2 mice developed worse cardiac dysfunction post-MI by boosting macrophage infiltration and inflammation. Overexpression of AMPKγ2 in macrophages repressed its migration and inflammation and alleviated myocardial injury. Mechanistically, CXCL16-CXCR6 axis was the contributor to macrophage migration, which was alleviated by AMPKγ2 via transcriptional regulation. Further, AMPKγ2 restrained YY1 expression, a key upstream transcription factor of CXCL16, to block the migration of macrophages. AMPKγ2 promoted YY1 degradation via smurf2 mediating ubiquitin-proteasome pathway depending on AMPKα1 subunit-mediating AMPK activity. Therefore, A769662 but not Metformin alleviated AMPKγ2 deficiency-induced migration and inflammation in macrophages. Finally, IFN-γ downregulated HOXA5 to repress AMPKγ2 transcriptional activity. Consistently, AMPKγ2 was dramatically declined in monocytes of MI patients compared to the control group. Conclusion: Macrophage AMPKγ2 deficiency played an important role in cardiac dysfunction following MI by activating the YY1-CXCL16-CXCR6 axis, which can be developed as a precision therapeutic target to ameliorate cardiac remodeling post-MI.

LncRNA KCNQ1OT1 contributes to hydrogen peroxide-induced apoptosis, inflammation, and oxidative stress of cardiomyocytes via miR-130a-3p/ZNF791 axis.

It has been reported that long noncoding RNA (lncRNA) KCNQ1 opposite strand/antisense transcript 1 (KCNQ1OT1) played an important role in myocardial infarction (MI). However, the regulatory network behind KCNQ1OT1 in MI is largely unknown. Quantitative real time polymerase chain reaction (qRT-PCR) was applied to detect the enrichment of KCNQ1OT1, microRNA-130a-3p (miR-130a-3p) and zinc finger 791 (ZNF791). The viability and apoptosis of AC16 cells were measured by (4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was conducted to assess the inflammation and oxidative stress status of AC16 cells. The targeted relationship between miR-130a-3p and KCNQ1OT1 or ZNF791 was predicted by StarBase bioinformatic database, and dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were carried out to verify these predictions. Hydrogen peroxide (H2 O2 ) stimulation caused a significant upregulation in the expression of KCNQ1OT1, while the level of miR-130a-3p showed an opposite phenomenon. KCNQ1OT1 was a crucial downstream component in H2 O2 -mediated toxic effects, and KCNQ1OT1 accelerated H2 O2 -induced toxic effects in AC16 cells. KCNQ1OT1 could sponge miR-130a-3p and down-regulate its expression. MiR-130a-3p exerted opposite effects to KCNQ1OT1, and the depletion of miR-130a-3p attenuated the protective effects of KCNQ1OT1 intervention on AC16 cells exposed to H2 O2 . MiR-130a-3p could bind to ZNF791, and ZNF791 served as the target of miR-130a-3p to promote H2 O2 -induced injury of AC16 cells. ZNF791 was modulated by KCNQ1OT1/miR-130a-3p signaling in H2 O2 -treated AC16 cells. In all, lncRNA KCNQ1OT1 deteriorated H2 O2 -mediated injury in cardiomyocytes through upregulating ZNF791 via serving as a molecular sponge for miR-130a-3p.

Exosomes in Myocardial Infarction: Therapeutic Potential and Clinical Application.

Myocardial infarction (MI) remains the leading fatal disease in the world, and with subsequent adverse ventricular remodeling often leading to the development of heart failure, finding new ways to improve the prognosis of MI is important. Exosomes are extracellular vesicles of 30-150nm secreted by various cells in the body. It is now well recognized that exosomes play an important role in MI, and exosomes may become a new approach to post-MI treatment. It is valuable to study how exosomes are involved in post-MI progression and how exosomes can be modified to improve their effectiveness. In this review, we focus on summarizing the therapeutic potential of exosomes for MI and the current status of clinical applications to provide evidence for the formal use of exosomes in the clinic.

MiR-182-5p Mediated by Exosomes Derived From Bone Marrow Mesenchymal Stem Cell Attenuates Inflammatory Responses by Targeting TLR4 in a Mouse Model of Myocardial Infraction.

Exosomes derived from mesenchymal stem cells (MSCs) could protect against myocardial infarction (MI). TLR4 is reported to play an important role in MI, while microRNA-182-5p (miR-182-5p) negatively regulates TLR4 expression. Therefore, we hypothesize that MSCs-derived exosomes overexpressing miR-182-5p may have beneficial effects on MI. We generated bone marrow mesenchymal stem cells (BM-MSCs) and overexpressed miR-182-5p in these cells for exosome isolation. H2O2-stimulated neonatal mouse ventricle myocytes (NMVMs) and MI mouse model were employed, which were subjected to exosome treatment. The expression of inflammatory factors, heart function, and TLR4 signaling pathway activation were monitored. It was found that miR-182-5p decreased TLR4 expression in BM-MSCs and NMVMs. Administration of exosomes overexpressing miR-182-5p to H2O2-stimulated NMVMs enhanced cell viability and suppressed the expression of inflammatory cytokines. In addition, they promoted heart function, suppressed inflammatory responses, and de-activated TLR4/NF-κB signaling pathway in MI mice. In conclusion, miR-182-5p transferred by the exosomes derived from BM-MSCs protected against MI-induced impairments by targeting TLR4.

Advanced research on the regulated necrosis mechanism in myocardial ischemia-reperfusion injury

Myocardial ischemia-reperfusion injury is an important factor that seriously affects the prognosis of patients with myocardial infarction. It can cause myocardial stun, no-reflow phenomenon, reperfusion arrhythmia, and even irreversible cardiomyocyte death. Regulated necrosis is a newly discovered type of regulatory cell death that is different from apoptosis, including necroptosis, pyrolysis, iron death and other forms. Regulated necrosis plays an important role in myocardial infarction, heart failure and other cardiovascular diseases, as well as myocardial ischemia-reperfusion injury and other pathophysiological processes, and is expected to become a new target for intervention in this type of disease.

A cross sectional study of acute myocardial infarction in young individuals below 40 years and associated risk factors in Mandya institute of medical sciences, Mandya, Karnataka

Background: Acute coronary syndrome (ACS) is a potentially life‑threatening condition which is more common in elderly people, and young are relatively protected. Its incidence in young Indians is about 12-16%. Currently, the protective effect on young from coronary artery disease (CAD) is taken away by several risk factors. The aim of this study is to determine the conventional and new emerging risk factors like hyperhomocysteinemia and lipoprotein a (Lp [a]) which are suggested to play an important role in myocardial infarction (MI). Methods: This study was a hospital‑based retrospective cross‑sectional analytical study involving 61 patients aged ≤40years presented with signs and symptoms of ACS confirmed by ECG changes and cardiac enzyme levels admitted in the cardiac ICU from April 2019 to March 2020.Results: Although ACS is a less common entity in young adults aged ≤40 years, smoking was the most common cause of the MI (75%) in young adults. Homocysteine and Lp (a) should be measured in young MI patients. Smoking cessation and prevention of diabetes and hypertension (HTN) should be encouraged.Conclusions: Smoking was the most common cause of the MI (75%) in young adults and is the major modifiable risk factor for MI in very young patients which needs strict prevention. Young patients with CAD were mainly males. There is a need for early detection of a risk factor to prevent the progression of ACS,

PCSK9 regulates pyroptosis via mtDNA damage in chronic myocardial ischemia.

Proprotein convertase subtilisin/Kexin type 9 (PCSK9) and pyroptosis both play important roles in myocardial infarction. This study was designed to test the hypothesis that PCSK9 regulates pyroptosis in cardiomyocytes during chronic myocardial ischemia. Primary cardiomyocytes were isolated from WT and PCSK9-/- mice. HL-1 cardiomyocytes were used to set up PCSK9-deficient (PCSK9-/-) and PCSK9-upregulated (PCSK9CRISPRa) cardiomyocyte cell line with CRISPR/Cas9 knockout or activation plasmid. Additional studies were performed with chronic myocardial ischemia in WT and PCSK9-/- mice. We observed that PCSK9 initiates mitochondrial DNA (mtDNA) damage, activates NLRP3 inflammasome signaling (NLRP3, ASC, Caspase-1, IL-1β, and IL-18), and subsequently induces Caspase-1-dependent pyroptosis. There was an intense expression of PCSK9 and pyroptosis marker, GSDMD-NT, in the zone bordering the infarct area. PCSK9-/- significantly suppressed expression of NLRP3 inflammasome signaling, GSDMD-NT, and LDH release. Furthermore, serum levels of PCSK9, NLPR3 inflammasome signaling, and pyroptosis (GSDMD and LDH release) were significantly elevated in patients with chronic myocardial ischemia as compared to those in age-matched healthy subjects. Human hearts with recent infarcts also showed high expression of PCSK9 and GSDMD-NT in the border zone similar to that in the infarcted mouse heart. These observations provide compelling evidence for the role ofPCSK9 in regulating Caspase-1-dependent pyroptosis via mtDNA damage and may qualify pro-inflammatory cytokines and pyroptosis as potential targets to treat PCSK9-related cardiovascular diseases.

Ginsenoside Rg3 alleviates inflammation in a rat model of myocardial infarction via the SIRT1/NF-κB pathway.

Inflammation serves an important role in myocardial infarction (MI). Ginsenoside Rg3 (Rg3), an activator of sirtuin 1 (SIRT1), has been identified to elicit anti-inflammatory effects via the NF-κB pathway. However, the function of Rg3 in MI remains unknown. In the present study, a MI rat model was established by coronary artery ligation and treated with Rg3 to explore whether Rg3 could inhibit inflammation in MI rats by inhibiting the SIRT1/NF-κB pathway. At 28 days post-MI, it was identified that Rg3 not only decreased the ST-segment ECG values in MI rats, but also significantly decreased serum LDH, CK-MB and cTnI levels in MI rats. In addition, Rg3 also significantly decreased serum tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 levels and increased serum IL-10 levels in MI rats. In the heart tissues of the MI rats, Rg3 attenuated myocardial pathological changes and cell apoptosis caused by MI, decreased the gene expression levels of TNF-α, IL-1β and IL-6, but increased the gene expression level of IL-10. In addition, the expression levels of the SIRT1 and transcription factor RelB proteins were significantly increased following Rg3 treatment, and the expression level of p-p65/p65 protein was significantly decreased in the heart tissues of MI rats with Rg3 treatment compared with that in heart tissues of MI rats without Rg3 treatment. In conclusion, Rg3 alleviates inflammation in a rat model of MI via the SIRT1/NF-κB pathway.

Cardiac Shock Wave Therapy Attenuates Cardiomyocyte Apoptosis after Acute Myocardial Infarction in Rats

Background/Aims: Researches have showed that cardiac shock wave therapy (CSWT) could improve left ventricular function and attenuate LV remodeling of the ischemic heart. Apoptosis plays an important role in myocardial infarction and determines heart function and prognosis. However, it is still not clear whether CSWT is sufficient to attenuate acute myocardial infarction (AMI) induced cardiomyocyte apoptosis in vivo. In this study, we used a rat model to examine whether CSWT could attenuate cardiomyocyte apoptosis after AMI and to explore potential mechanisms. Methods: We generated an AMI rat model to investigate the function and possible regulatory mechanisms of CSWT. All rats were randomly divided into four groups: the sham-operated only group, sham-operated with SW treatment group, AMI only group, and AMI treated with SW treatment group.The rats were treated with a left anterior descending coronary artery ligation for 12h and then treated with or without CSWT (800 shots at 0.1 mJ/ mm²). Cytochrome c release was measured to analyze mitochondrial function and integrity. The apoptotic cell rate was determined by TUNEL assay. Western blot was used to analyze the cell apoptosis-, inflammation-, and survival-related signaling pathways. Results: First, the methodology of CSWT in the rat model of AMI was established. Second, CSWT attenuated the cardiomyocyte apoptosis rate in the infarct border zone. Third, CSWT suppressed the expression of apoptosis and inflammation molecules after AMI. Fourth, CSWT inhibited activation of the JNK pathway, which indicated inhibition of the cell inflammatory pathways and promotion of cardiomyocyte survival after AMI. Conclusion: These results indicate that CSWT exerts a protective effect against AMI-induced cardiomyocyte apoptosis, potentially by attenuating cytochrome c release from the mitochondria and inhibiting of the mitochondrial-dependent intrinsic apoptotic pathway. We also demonstrate that CSWT suppresses the JNK pathway and cardiomyocyte inflammation, which may also decrease cardiomyocyte apoptosis in vivo.

Bioinformatics analysis of key genes and signaling pathways associated with myocardial infarction following telomerase activation.

The present study aimed to identify key genes and signaling pathways associated with myocardial infarction (MI) following telomerase activation, and investigate the possible underlying molecular mechanisms involved in this process. Array data of GSE62973 was downloaded, including 11 samples from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were analyzed in infarct vs. control, infarct + telomerase vs. control, and infarct + telomerase vs. infarct with the Linear Models for Microarray and RNA‑Seq Data package. Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed for upregulated and downregulated genes by the Database for Annotation, Visualization and Integrated Discovery. Sub network modules of 3 protein‑protein interaction (PPI) networks were analyzed by Clustering with Overlapping Neighbourhood Expansion, and genes associated with telomerase were analyzed. Proto‑oncogene tyrosine‑protein kinase Src (Src) and proto‑oncogene tyrosine‑protein kinase Fyn (Fyn) were the hub nodes of the greatest degree in the PPI network for the infarct+telomerase vs. control comparison group and infarct+telomerase vs. infarct comparison group, respectively. Olfactory receptor gene family associated genes, including olfactory receptor 10 were significantly enriched in the sub network modules of the 3 comparison groups. In addition, olfactory transduction was a significantly enriched pathway by downregulation of DEGs in the infarct vs. control comparison group, and was additionally a significantly enriched pathway by upregulated DEGs in infarct + telomerase vs. infarct comparison group. Olfactory transduction was a significant pathway enriched by genes associated with telomerase. Telomerase activation may serve an important role in MI, in part, via the regulation of Src, Fyn and olfactory receptor family associated genes.

A study of risk factors for acute myocardial infarction in patients below 35 years in eastern India

Background: Coronary artery disease (CAD) is most common cause of mortality. Its incidence in young Indians is about 12%–16%. Myocardial infarction (MI) in young can be divided into two groups, those with angiographically normal coronaries and those with CAD. 15%–20% of those with CAD have no identifiable risk factors and therefore miss the opportunity for primary prevention. Recent reports have suggested that increased lipoprotein a (Lp[a]) and hyperhomocysteinemia play an important role in MI. The true prevalence of CAD in young is grossly underestimated.Aims: (1) Study of risk factors for MI in patients <35 years. (2) Clinical presentation. (3) Disease pattern in coronary angiography. (4) To assess the relationship of emerging risk factors such as homocysteine and Lp(a) with MI.Materials and Methods: Fifty patients aged 35 years or younger diagnosed with acute MI were included.Results: The majority of patients were males (80%). The mean age was 33.3 in males and 31.8 years in females. Chest pain was the most common presenting complaint (94%). Smoking was the most prevalent risk factor (72%). Hyperhomocysteinemia (42%) and raised Lp(a) (24%) were emerging risk factors. Anterior wall MI was most prevalent (64%) and most patients had single vessel disease with left descending coronary being the most commonly involved artery.Conclusions: Homocysteine and Lp(a) should be measured in young MI patients. Smoking cessation and prevention of diabetes and hypertension should be encouraged. As young patients have more discrete lesion, timely revascularization will reduce myocardial damage.

High Sensitivity C-Reactive Protein an inflammatory marker and lipoprotein levels in patients with coronary heart disease

Background: C-Reactive Protein is a good marker of systemic inflammation which can be measured easily. Atherosclerosis lesions are intimal thickening of arteries. Inflammatory and immune cells constitute an important part of atheroma. C-RP levels at the upper end of the normal range indicate that a low level of inflammatory response has been initiated. Measurment of hs CRP provides a method to assess the risk of cardiovascular disease very early in life. Aim: Estimation of High sensitivity C-Reactive Protein (HS-CRP) levels which is a marker of inflammation in serum of normal people and patients with past history of myocardial infarction. Materials and Methods: Twenty six serum samples from patients with coronary heart disease (who had previous history of Myocardial Infarction) and twenty-one control samples and were included in the study. High sensitivity C-reactive protein and lipoprotein profile were estimated in patients with coronary heart disease and in age matched controls. Statistical Analysis- All data were represented as mean ± SD. Experimental data were statistically analyzed by students t’-test. For all analysis statistical significance was considered as p &lt; 0.05. Results: Mean hs C-RP level is significantly elevated in patients who had myocardial infarction when compared with age matched controls. Total cholesterol, LDL cholesterol also found to be increased in individuals who had myocardial infarction. Conclusion: Inflammation plays an important role in myocardial infarction. Increased risk of MI is seen in those individuals who have higher levels of hsC-RP. There is also increase in total cholesterol and LDL cholesterol in subjects who had myocardial infarction when compared to controls. Coronary artery disease may be prevented by reducing the inflammation in addition to reducing the LDL cholesterol

Unbalanced Oxidant-Antioxidant Status: A Potential Therapeutic Target for Coronary Chronic Total Occlusion in Very Old Patients.

Unbalanced oxidant and antioxidant status played an important role in myocardial infarction. The present study was a clinical trial combined preclinically with targeted agent against cardiovascular injuries and ischemia in vivo model. We tried to confirm the association of unbalanced oxidant and antioxidant status with coronary chronic total occlusion (CTO) in 399 very old patients (80~89 years) and investigated the potential therapeutic value of purified polysaccharide from endothelium corneum gigeriae galli (PECGGp). We analyzed levels of circulating superoxide dismutase 3 (SOD3), nitric oxide (NO), endothelial nitric oxide synthase (eNOS), and malondialdehyde (MDA) in very old patients with coronary CTO. Levels of SOD3, NO, eNOS, and MDA in the cardiac tissue were measured in myocardial infarction rats. Levels of SOD3, eNOS, and NO were lowered (p < 0.001) and levels of MDA were increased (p < 0.001). PECGGp treatment increased levels of SOD3, eNOS, and NO (p < 0.01) in cardiac tissue, while decreasing levels of MDA (p < 0.01). PECGGp may suppress unbalanced oxidant and antioxidant status in infarcted myocardium by inhibiting levels of MDA and elevating NO, eNOS, and SOD3 levels. PECGGp could be considered as a potential therapeutic agent for coronary CTO in very old patients.

The Importance of the Troponin Biomarker in Myocardial Infarction

The significant increase of deaths due to myocardial infarction (MI) is directly related to lifestyle and the increase of the level of its risk factors. The efforts of researchers have recently focused on finding ways to prevent and reduce the damages occurred after the occurrence of MI. Currently, the focus on measuring cardiac biomarkers has an important role in early diagnosis and prevention of irreparable damages of cardiac myocard. This study has explored the cardiac biomarkers troponin I (TnI) and troponin T (TnT) in terms of structures and their important role in MI. Also, the importance of measuring troponin, measurement methods and a comparison among different measurement methods are pointed out. Finally, the new methods and approaches for measuring and comparing new measurement methods, their advantages and properties are mentioned.

Functional Network Analysis Reveals Versatile MicroRNAs in Human Heart

Background: Acting on many mRNAs allows the power of a single miRNA to modulate multiple pathophysiological phenotypes. One question is whether versatile miRNAs exist in the pathological scenarios of myocardial infarction (MI) and heart failure (HF). Methods: A hypergeometric analysis, in combination with network-based functional analyses, was performed on the available human protein interaction and miRNA-gene association data to highlight versatile miRNAs among the significantly dysregulated miRNAs in MI and HF. In vivo, mice models of MI and HF were then established to investigate whether dysregulated expression be undertaken by versatile miRNA identified here. Results: Systematic analyses really identified the previously validated miRNAs that have been verified of multiple important roles in MI and HF, demonstrating method effectiveness. By using this means, we innovatively revealed the vital role of miR-7 in maintaining the dynamic balance of protein interactions and its obvious overexpression in MI and HF that implies pathological involvement. Functional experiments are definitely needed for further revealing its potential influences on MI- or HF-led myocardial injury. Conclusion: Our results have implications not only for the coming miRNA-based strategy in treating MI and HF but also for further understanding on gene regulation by miRNAs in human heart.

Endothelial cells but not platelets are the major source of Toll-like receptor 4 in the arterial thrombosis and tissue factor expression in mice.

It is known that Toll-like receptor (TLR)-4 plays an important role in myocardial infarction and atherothrombosis. The role of TLR-4 in arterial thrombosis is undefined. Both TLR-4-deficient (TLR-4(-/-)) and wild-type (WT) mice were subjected to FeCl3 carotid artery injury, and the time required to form an occlusive thrombus was measured. The mean time to occlusion in TLR-4(-/-) mice was significantly greater than that in WT mice after injury (303 ± 32 vs. 165 ± 34 s, P < 0.05). Furthermore, when we used a WT or TLR-4(-/-)-derived platelet reinfusion in a platelet depletion/reinfusion procedure, there was no significant change in the occlusion time and tissue factor (TF) activity in injured arteries between WT mice and platelet-depleted WT mice. Similarly, no significant difference was observed between TLR-4(-/-) mice and platelet-depleted TLR-4(-/-) mice for the WT or TLR-4(-/-)-derived platelet reinfusion. However, TF expression and activity were significantly reduced in the vascular wall of TLR-4(-/-) mice compared with WT mice. In vivo, lipopolysaccharide accelerated the occlusion time in WT mice but not TLR-4(-/-) mice. In vitro, LPS-induced TF activity was reduced in endothelial cells of TLR-4(-/-) mice relative to WT mice. The data demonstrate that TLR-4 contributes to arterial thrombosis formation in vivo and causes increased TF expression and activity in vitro. The results further suggest that the stimulation is mainly derived by endothelial cells but is not due to platelet-derived TLR-4.

Cardioprotective effects of adipokine apelin on myocardial infarction

Angiogenesis plays an important role in myocardial infarction. Apelin and its natural receptor (angiotensin II receptor-like 1, AGTRL-1 or APLNR) induce sprouting of endothelial cells in an autocrine or paracrine manner. The aim of this study is to investigate whether apelin can improve the cardiac function after myocardial infarction by increasing angiogenesis in infarcted myocardium. Left ventricular end-diastolic pressure (LVEDP), left ventricular end systolic pressure (LVESP), left ventricular developed pressure (LVDP), maximal left ventricular pressure development (±LVdp/dtmax), infarct size, and angiogenesis were evaluated to analyze the cardioprotective effects of apelin on ischemic myocardium. Assays of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 5-bromo-2'-deoxyuridine incorporation, wound healing, transwells, and tube formation were used to detect the effects of apelin on proliferation, migration, and chemotaxis of cardiac microvascular endothelial cells. Fluorescein isothiocyanate-labeled bovine serum albumin penetrating through monolayered cardiac microvascular endothelial cells was measured to evaluate the effects of apelin on permeability of microvascular endothelial cells. In vivo results showed that apelin increased ±LV dp/dtmax and LVESP values, decreased LVEDP values (all p < 0.05), and promoted angiogenesis in rat heart after ligation of the left anterior descending coronary artery. In vitro results showed that apelin dose-dependently enhanced proliferation, migration, chemotaxis, and tube formation, but not permeability of cardiac microvascular endothelial cells. Apelin also increased the expression of vascular endothelial growth factor receptors-2 (VEGFR2) and the endothelium-specific receptor tyrosine kinase (Tie-2) in cardiac microvascular endothelial cells. These results indicated that apelin played a protective role in myocardial infarction through promoting angiogenesis and decreasing permeability of microvascular endothelial cells via upregulating the expression of VEGFR2 and Tie-2 in cardiac microvascular endothelial cells.

Stem Cell Antigen 1 Protects Against Cardiac Hypertrophy and Fibrosis After Pressure Overload

Stem cell antigen (Sca) 1, a glycosyl phosphatidylinositol-anchored protein localized to lipid rafts, is upregulated in the heart during myocardial infarction and renovascular hypertension-induced cardiac hypertrophy. It has been suggested that Sca-1 plays an important role in myocardial infarction. To investigate the role of Sca-1 in cardiac hypertrophy, we performed aortic banding in Sca-1 cardiac-specific transgenic mice, Sca-1 knockout mice, and their wild-type littermates. Cardiac hypertrophy was evaluated by echocardiographic, hemodynamic, pathological, and molecular analyses. Sca-1 expression was upregulated and detected in cardiomyocytes after aortic banding surgery in wild-type mice. Sca-1 transgenic mice exhibited significantly attenuated cardiac hypertrophy and fibrosis and preserved cardiac function compared with wild-type mice after 4 weeks of aortic banding. Conversely, Sca-1 knockout dramatically worsened cardiac hypertrophy, fibrosis, and dysfunction after pressure overload. Furthermore, aortic banding-induced activation of Src, mitogen-activated protein kinases, and Akt was blunted by Sca-1 overexpression and enhanced by Sca-1 deficiency. Our results suggest that Sca-1 protects against cardiac hypertrophy and fibrosis via regulation of multiple pathways in cardiomyocytes.