• Korean Circulation Journal
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• v.53 no.3
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• pp.151-167
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• 2023

Background and Objectives: Acute myocardial infarction (AMI) often occurs suddenly and leads to fatal consequences. Ferroptosis is closely related to the progression of AMI. However, the specific mechanism of ferroptosis in AMI remains unclear. Methods: We constructed a cell model of AMI using AC16 cells under oxygen and glucose deprivation (OGD) conditions and a mice model of AMI using the left anterior descending (LAD) ligation. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide was employed to determine cell viability. The levels of lactate dehydrogenase, creatine kinase, reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and iron were measured using corresponding kits. Dual luciferase reporter gene assay, RNA-binding protein immunoprecipitation, and RNA pull-down were performed to validate the correlations among AC005332.7, miR-331-3p, and cyclin D2 (CCND2). Hematoxylin and eosin staining was employed to evaluate myocardial damage. Results: AC005332.7 and CCND2 were lowly expressed, while miR-331-3p was highly expressed in vivo and in vitro models of AMI. AC005332.7 sufficiency reduced ROS, MDA, iron, and ACSL4 while boosting the GSH and GPX4, indicating that AC005332.7 sufficiency impeded ferroptosis to improve cardiomyocyte injury in AMI. Mechanistically, AC005332.7 interacted with miR-331-3p, and miR-331-3p targeted CCND2. Additionally, miR-331-3p overexpression or CCND2 depletion abolished the suppressive impact of AC005332.7 on ferroptosis in OGD-induced AC16 cells. Moreover, AC005332.7 overexpression suppressed ferroptosis in mice models of AMI. Conclusions: AC005332.7 suppressed ferroptosis in OGD-induced AC16 cells and LAD ligation-operated mice through modulating miR-331-3p/CCND2 axis, thereby mitigating the cardiomyocyte injury in AMI, which proposed novel targets for AMI treatment.

• The Korean Journal of Nuclear Medicine
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• v.27 no.2
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• pp.191-194
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• 1993

Apparent washout of T1-201 may occur between redistribution and reinjection images. To examine the frequency of it, we prospectively compared 4-hour redistribution and reinjection images in 63 consequent patients. All patients underwent pharmacological stress test using 0.56 mg/kg dipyridamole. Immediately after the 4-hour redistribution images, 1 mCi T1-201 was injected at rest, and images were reacquired 10 minutes after reinjection. The stress, redistribution, and reinjection images were then analyzed semiquantitatively (0=no uptake, 1=faint uptake, 2=mildly diminished uptake, 3=normal uptake). Of the 100 abnormal myocardial regions on the stress images, 54 showed either complete or partial reversibility on 4-hour redistribution images. After reinjection 11(21.2%) of these regions demonstrated apparent T1-201 washout due to low differential uptake of the tracer. Such lesions would appear irreversible if redistribution imaging is not performed before reinjection. Thus 4-hour redistribution imaging should be performed for assessment of myocardial ischemia and viability.

• Molecules and Cells
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• v.19 no.3
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• pp.402-407
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• 2005

Bone marrow mesenchymal stem cells (MSCs) have shown potential for cardiac repair following myocardial injury, but this approach is limited by their poor viability after transplantation. To reduce cell loss after transplantation, we introduced the fibroblast growth factor-2 (FGF-2) gene ex vivo before transplantation. The isolated MSCs produced colonies with a fibroblast-like morphology in 2 weeks; over 95% expressed CD71, and 28% expressed the cardiomyocyte-specific transcription factor, Nkx2.5, as well as ${\alpha}$-skeletal actin, Nkx2.5, and GATA4. In hypoxic culture, the FGF-2-transfected MSCs (FGF-2-MSCs) secreted increased levels of FGF-2 and displayed a threefold increase in viability, as well as increased expression of the anti-apoptotic gene, Bcl2, and reduced DNA laddering. They had functional adrenergic receptors, like cardiomyocytes, and exposure to norepinephrine led to phosphorylation of ERK1/2. Viable cells persisted 4 weeks after implantation of $5.0{\times}10^5$ FGF-2-MSCs into infarcted myocardia. Expression of cardiac troponin T (CTn T) and a voltage-gated $Ca^{2+}$ channel (CaV2.1) increased, and new blood vessels formed. These data suggest that genetic modification of MSCs before transplantation could be useful for treating myocardial infarction and end-stage cardiac failure.

• IMMUNE NETWORK
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• v.22 no.6
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• pp.49.1-49.15
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• 2022

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.

• Journal of Microbiology and Biotechnology
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• v.31 no.8
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• pp.1069-1078
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• 2021

Sevoflurane postconditioning (SPostC) has been proved effective in cardioprotection against myocardial ischemia/reperfusion injury. It was also reported that heat shock protein 70 (HSP70) could be induced by sevoflurane, which played a crucial role in hypoxic/reoxygenation (HR) injury of cardiomyocytes. However, the mechanism by which sevoflurane protects cardiomyocytes via HSP70 is still not understood. Here, we aimed to investigate the related mechanisms of SPostC inducing HSP70 expression to reduce the HR injury of cardiomyocytes. After the HR cardiomyocytes model was established, the cells transfected with siRNA for HSP70 (siHSP70) or not were treated with sevoflurane during reoxygenation. The lactate dehydrogenase (LDH) level was detected by colorimetry while cell viability and apoptosis were detected by MTT and flow cytometry. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting were used to detect HSP70, apoptosis-, cell cycle-associated factors, iNOS, and Cox-2 expressions. Enzyme-linked immuno sorbent assay (ELISA) was used to measure malondialdehyde (MDA) and superoxide dismutase (SOD). SPostC decreased apoptosis, cell injury, oxidative stress and inflammation and increased viability of HR-induced cardiomyocytes. In addition, SPostC downregulated Bax and cleaved caspase-3 levels, while SPostC upregulated Bcl-2, CDK-4, Cyclin D1, and HSP70 levels. SiHSP70 had the opposite effect that SPostC had on HR-induced cardiomyocytes. Moreover, siHSP70 further reversed the effect of SPostC on apoptosis, cell injury, oxidative stress, inflammation, viability and the expressions of HSP70, apoptosis-, and cell cycle-associated factors in HR-induced cardiomyocytes. In conclusion, this study demonstrates that SPostC can reduce the HR injury of cardiomyocytes by inducing HSP70 expression.

• The Korean Journal of Physiology and Pharmacology
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• v.26 no.5
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• pp.325-333
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• 2022

Heart failure (HF) has become one of the severe public health problems. The detailed role of mitochondrial function in HF was still unclear. Benzoylaconine (BAC) is a traditional Chinese medicine, but its role in HF still needs to be explored. In this study, oxygen-glucose deprivation and reperfusion (OGD/R) was executed to mimic the injury of H9C2 cells in HF. The viability of H9C2 cells was assessed via MTT assay. OGD/R treatment markedly decreased the viability of H9C2 cells, but BAC treatment evidently increased the viability of OGD/R-treated H9C2 cells. The apoptosis of H9C2 was enhanced by OGD/R treatment but suppressed by BAC treatment. The mitochondrial membrane potential was evaluated via JC-1 assay. BAC improved the mitochondrial function and suppressed oxidative stress in OGD/R-treated H9C2 cells. Moreover, Western blot analysis revealed that the protein expression of p-AMPK and PGC-1α were reduced in OGD/R-treated H9C2 cells, which was reversed by BAC. Rescue assays indicated that AMPK attenuation reversed the BAC-mediated protective effect on OGD/R-treated cardiomyocytes. Moreover, BAC alleviated myocardial injury in vivo. In a word, BAC modulated the mitochondrial function in OGD/R-induced cardiomyocyte injury by activation of the AMPK/PGC-1 axis. The findings might provide support for the application of BAC in the treatment of HF.

• The Korean Journal of Nuclear Medicine
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• v.26 no.2
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• pp.274-279
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• 1992

Clinical role of $^{99m}Tc-MIBI$ myocardial scintigraphy in the diagnosis of coronary artery disease (CAD) is now well accepted, however, the role of it in the identification of viable myocardium in patients with chronic CAD has not yet been clarified. To determine the usefulness of rest-injected $^{99m}Tc-MIBI$ scan as a marker of myocardial viability, the regional uptake of this agent at rest was compared with that of $^{201}Tl$ on reinjection and 24 hours after reinjection images. Subject patients were 13 chronic CAD patients who showed irreversible perfusion defect(s) on standard pharmacologic (dipyridamole) stress-redistribution images. Immediately after the redistribution images were obtained, 37 MBq thallium was injected at rest, and images were reacquired at 10 minutes and 24 hours after reinjection. After then 740 MBq $^{99m}Tc-MIBI$ was injected, and 1 hour later rest MIBI myocardial imaging was performed. Five sets of imagestress, redistribution, reinjection, delayed images of thallium, and rest image of MIBI) were then analyzed qualitatively and quantitatively. Left ventricle was arbitrarily divided into 9 segments (apex, basal and apical portions of anterior, septal, inferior, and lateral walls). Seven patients and 30 regions showed a fixed perfusion defect on the stress-redistribution images. Among 30 regions, 15 showed positive uptakes and 6 showed negative uptakes on both $^{201}Tl$ reinjection/delayed images and $^{99m}Tc-MIBI$ rest images. Five regions showed only thallium uptake and were regarded as viable clinically. Of four regions which showed only $^{99m}Tc-MIBI$ uptake, two were regarded as viable, while the other two were regarded as a nonviable scar tissue clinically. In conclusion, $^{201}Tl$ reinjection technique was more reliable in the identification of viable myocardium. However, the role of $^{99m}Tc-MIBI$ in identification of viable myocardium was still remained to be clarified because 2 of 9 regions showed only $^{99m}Tc-MIBI$ uptake and were regarded as viable tissues.

• Journal of Ginseng Research
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• v.47 no.6
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• pp.755-765
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• 2023

Background: Caveolin-1, the scaffolding protein of cholesterol-rich invaginations, plays an important role in store-operated Ca²⁺ influx and its phosphorylation at Tyr14 (p-caveolin-1) is vital to mobilize protection against myocardial ischemia (MI) injury. SOCE, comprising STIM1, ORAI1 and TRPC1, contributes to intracellular Ca²⁺ ([Ca²⁺]_i) accumulation in cardiomyocytes. The purified extract of steamed Panax ginseng (EPG) attenuated [Ca²⁺]_i overload against MI injury. Thus, the aim of this study was to investigate the possibility of EPG affecting p-caveolin-1 to further mediate SOCE/[Ca²⁺]_i against MI injury in neonatal rat cardiomyocytes and a rat model. Methods: PP2, an inhibitor of p-caveolin-1, was used. Cell viability, [Ca²⁺]_i concentration were analyzed in cardiomyocytes. In rats, myocardial infarct size, pathological damages, apoptosis and cardiac fibrosis were evaluated, p-caveolin-1 and STIM1 were detected by immunofluorescence, and the levels of caveolin-1, STIM1, ORAI1 and TRPC1 were determined by RT-PCR and Western blot. And, release of LDH, cTnI and BNP was measured. Results: EPG, ginsenosides accounting for 57.96%, suppressed release of LDH, cTnI and BNP, and protected cardiomyocytes by inhibiting Ca²⁺ influx. And, EPG significantly relieved myocardial infarct size, cardiac apoptosis, fibrosis, and ultrastructure abnormality. Moreover, EPG negatively regulated SOCE via increasing p-caveolin-1 protein, decreasing ORAI1 mRNA and protein levels of ORAI1, TRPC1 and STIM1. More importantly, inhibition of the p-caveolin-1 significantly suppressed all of the above cardioprotection of EPG. Conclusions: Caveolin-1 phosphorylation is involved in the protective effects of EPG against MI injury via increasing p-caveolin-1 to negatively regulate SOCE/[Ca²⁺]_i.

• The Korean Journal of Nuclear Medicine
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• v.39 no.4
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• pp.224-230
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• 2005

Purpose: The maximal elastance ($E_{max}$) of myocardium has been established as a reliable load-independent contractility index. Recently, we developed a noninvasive method to measure the regional contractility using gated myocardial SPECT and arterial tonometry data. In this study, we measured regional $E_{max}(rE_{max}$ in the patients who underwent coronary artery bypass graft surgery (CABG), and assessed its relationship with other variables. Materials and Methods: 21 patients (M:F=17:4, $58{\pm}12$ y) who underwent CABG were enrolled. $^{201}TI$ rest/dipyridamole stress $^{99m}Tc$-sestamibi gated SPECT were performed before and 3 months after CABG. For 15 myocardial regions, regional time-elastance curve was obtained using the pressure data of tonometry and the volume data of gated SPECT. To investigate the coupling with myocardial function, preoperative regional $E_{max}$ was compared with regional perfusion and systolic thickening. In addition, the correlation between $E_{max}$ and viability was assessed in dysfunctional segments (thickening <20% before CABG). The viability was defined as improvement of postoperative systolic thickening more than 10%. Results: Regional $E_{max}$ was slightly increased after CABG from $2.41{\pm}1.64 (pre)\;to\;2.78{\pm}1.83 (post)$ mmHg/ml. $E_{max}$ had weak correlation with perfusion and thickening (r=0.35, p<0.001). In the regions of preserved perfusion (${\geq}60%$), $E_{max}$ was $2.65{\pm}1.67$, while it was $1.30{\pm}1.24$ in the segments of decreased perfusion. With regard to thickening, $E_{max}$ was $3.01{\pm}1.92$ mmHg/ml for normal regions (thickening ${geq}40%$), $2.40{\pm}1.19$ mmHg/ml for mildly dysfunctional regions (<40% and ${\geq}20%$), and $1.13{\pm}0.89$ mmHg/ml for severely dysfunctional regions (<20%). $E_{max}$ was improved after CABG in both the viable (from $1.27{\pm}1.07\;to\;1.79{\pm}1.48$ mmHg/ml) and non-viable segments (from $0.97 {\pm}0.59\;to\;1.22{\pm}0.71$ mmHg/ml), but there was no correlation between $E_{max}$ and thickening improvements (r=0.007). Conclusions: Preoperative regional $E_{max}$ was relatively concordant with regional perfusion and systolic thickening on gated myocardial SPECT. In dysfunctional but viable segments, $E_{max}$ was improved after CABG, but showed no correlation with thickening improvement. As a load-independent contractility index of dysfunctional myocardial segments, we suggest that the regional $E_{max}$ could be an independent parameter in the assessment of myocardial function.

• The Korean Journal of Nuclear Medicine
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• v.25 no.2
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• pp.177-185
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• 1991

Dipyridamole thallium imaging is one of the most widely accepted means of evaluating patients with suspected or known coronay artery disease. The results of thallium imaging help diagnose coronary artery disesse (CAD), determine the hemodynamic significance of coronary stenosis, evaluate viability of myocardium, assess the outcome of therapeutic interventions and stratify patients according to their risk for luther cardiac events. An increased lung thallium uptake and transient LV dilation has been reported as poor prognostic indicator and associated with extensive and severe coronary artery disease. We quantitated lung/heart uptake ratio (l/HUR) and transient left ventricular dilation ratio in 44 patients and 17 controls undertaking dipyridamole thallium-201 scintigraphy. The results are as follows: 1) The lung/heart uptake ratio was high in patients with CAD and which became higher according to increasing number of diseased vessel. The L/HUR of patients with low LVEF (<35%) was lower than those with normal LVEF. 2) Transient left ventricular dilation ratio of CAD patients had no close relation between numbers of diseased vessels and was not higher than normals. But transient left ventricular dilation ratio of patients with myocardial infartion was higher than normals. We concluded that lung/heart uptake ratio seems to be sensitive marker for severity of CAD and myocardial function, but transient left ventricular dilation ratio alone is not sufficient to be a marker for severe and extensive CAD.