Abstract 141: Inhibition of Coagulation Factor Xa Attenuates Myocardial Ischemia Reperfusion Injury in Mice

Background: Ischemic/reperfusion (I/R) injury substantially effects the outcome of myocardial infarction (MI). Current reperfusion therapy does not sufficiently prevent injury caused by microvascular thrombo-inflammation. Coagulation proteases mediate inflammation via protease activated receptors. FXa induced thrombin generation is the key step in the coagulation cascade. We hypothesize that inhibition of FXa by rivaroxaban attenuates I/R injury after MI. Methods: Male WT c57BL/6 mice (age 8-9 weeks, n=8 per group) underwent surgical ligation of the left anterior descending coronary artery 7 days prior to experimentation. Next, the ligature was tightened for 1h to induce ischemia and loosened either at 4h (early), or at 4 weeks (late), to allow reperfusion. The intervention consisted of 2 rivaroxaban (1.6 mg/kg) i.v.-injections or placebo (0.9%NaCl) after 15min of ischemia and 5min of reperfusion. In the early model. the area at risk (AAR) was visualized through Evans blue and differentiated from the area of infarction (AOI) through triphenyl tetrazolium chloride staining. Plasma cardiovascular markers were quantified using Luminex Multiplex. In the late model, LVEF was measured 10min pre-ischemia and 4 weeks’ post-reperfusion utilizing echocardiography. Results: The rivaroxaban treatment group showed signs of diminished myocardial damage as indicated by reduced median AOI/AAR (41%[IQR34-48] vs. control 62%[IQR52-67] p<0.001). This was supported by a better preserved LVEF after 4 weeks of reperfusion (25%[IQR19-31] vs. control (16%[IQR12-21]). Although not significantly different, plasma E-Selectin, PECAM-1, PAI-1, proMMP9, and thrombomodulin showed a trend to increased levels upon treatment with rivaroxaban. Conclusion: FXa inhibition by rivaroxaban significantly reduces myocardial I/R injury in mice and may provide long term preservation of LVEF. Raised cardiovascular markers suggest increased tissue remodeling and phenotypical alteration of endothelial cells after rivaroxaban treatment. These results suggest that coagulation proteases (i.e. FXa) play a relevant role in I/R injury during MI, most likely through activation of protease activated receptors.

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Role of ischemic preconditioning in cardioprotective mechanisms of mCRP deposited myocardium in a rat model

10.1101/2020.05.13.093989 ◽

2020 ◽

Author(s):

Eun Na Kim ◽

Jae-Sung Choi ◽

Chong Jai Kim ◽

So Ra Kim ◽

Ki-Bong Kim ◽

...

Keyword(s):

Coronary Artery ◽

Mrna Expression ◽

Ischemic Preconditioning ◽

Rat Model ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Myocardial Damage ◽

Study Groups ◽

Area At Risk ◽

Triphenyltetrazolium Chloride

AbstractThe deposition of monomeric C-reactive protein (mCRP) in the myocardium aggravates ischemia-reperfusion injury (IRI) and myocardial infarction. Ischemic preconditioning (IPC) is known to protect the myocardium against IRI. We evaluated the effects of IPC on mCRP-deposited myocardium due to IRI in a rat model. Myocardial IRI was produced by ligation of the coronary artery. Direct IPC was applied before IRI using multiple short direct occlusions of the coronary artery. CRP was infused intravenously after IRI. The study groups included the following: sham (n=3), IRI only (n=5), IRI+CRP (n=9), and IPC+IRI+CRP (n=6) groups. The infarct area and area at risk were assessed using Evans blue and 2,3,5-triphenyltetrazolium chloride (2,3,5-TTC) staining. Additionally, mCRP immunostaining and interleukin (IL)-6 mRNA reverse transcriptase-polymerase chain reaction (RT-PCR) were performed. In the IRI+CRP group, the infarcted area, mCRP deposition, and IL-6 mRNA expression were higher than those in the IRI only group. However, in the IPC+IRI+CRP group, the infarction (20% vs. 34% p=0.085) and mCRP myocardial deposition (21% vs. 44%, p=0.026) were lower and IL-6 mRNA expression was higher than those in the IRI+CRP group (fold change, 407 vs. 326, p=0.808), although this was not statistically significant. IPC has cardioprotective effects against myocardial damage caused by mCRP deposition. This protective effect is related to the increase in IL-6 mRNA expression.

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Abstract 289: Cardiac-Specific Ectonucleoside Triphosphate Diphosphohydrolase 1 Overexpression Affords Protection from Myocardial Infarction and Reperfusion Injury

Circulation Research ◽

10.1161/res.111.suppl_1.a289 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Zhaobin Xu ◽

Debra G Wheeler ◽

Shouvik D Mahamud ◽

Karen M Dwyer ◽

Simon C Robson ◽

...

Keyword(s):

Myocardial Ischemia ◽

Infarct Size ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Myocardial Infarct Size ◽

Area At Risk ◽

Tetrazolium Chloride ◽

Myocardial Ischemia Reperfusion

Background: During myocardial stress, extracellular levels of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) increase. These extracellular ATP and ADP levels are modulated via hydrolysis by ectonucleoside triphosphate diphosphohydrolase 1 (ENTDP-1/CD39) to adenosine monophosphate (AMP) subsequently converted by ecto-5'-nucleotidase (CD73) to the anti-thrombotic, cardioprotective nucleoside, adenosine. Previous data demonstrated significantly smaller infarcts in mice globally overexpressing CD39. The current objective was to determine whether tissue specific overexpression of CD39 in the heart would reduce myocardial ischemia/reperfusion injury. Methods: Myocardial ischemia/reperfusion (I/R) injury was evaluated in transgenic mice overexpressing human CD39 driven by the α-MHC promoter. I/R injury was induced by ligation of the left anterior descending (LAD) artery for 60 min followed by 24 hours of reperfusion. Myocardial infarct size was determined by staining with triphenyl tetrazolium chloride (TTC) and the area-at-risk was delineated by perfusion with 5% Phthalo Blue. Results: Expression of CD39 in the heart tissue was confirmed by Western blot analysis. In response to 60 minutes of ischemia followed by 24 hours of reperfusion, α-MHC CD39-OE animals displayed a marked reduction in infarct size (WT: 31.68%±4.64 vs TG: 6.14%± 2.48, N=5/group, P<0.01), relative to wild-type controls (Figure). Conclusions: Overexpression of CD39 in cardiac tissue alone significantly attenuates myocardial ischemic injury.

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Overexpression of miR-431 attenuates hypoxia/reoxygenation-induced myocardial damage via autophagy-related 3

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmaa154 ◽

2020 ◽

Author(s):

Kang Zhou ◽

Yan Xu ◽

Qiong Wang ◽

Lini Dong

Keyword(s):

Cell Viability ◽

Cell Apoptosis ◽

Myocardial Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Myocardial Damage ◽

Protective Role ◽

Human Cardiomyocytes ◽

Hypoxia Reoxygenation

Abstract Myocardial injury is still a serious condition damaging the public health. Clinically, myocardial injury often leads to cardiac dysfunction and, in severe cases, death. Reperfusion of the ischemic myocardial tissues can minimize acute myocardial infarction (AMI)-induced damage. MicroRNAs are commonly recognized in diverse diseases and are often involved in the development of myocardial ischemia/reperfusion injury. However, the role of miR-431 remains unclear in myocardial injury. In this study, we investigated the underlying mechanisms of miR-431 in the cell apoptosis and autophagy of human cardiomyocytes in hypoxia/reoxygenation (H/R). H/R treatment reduced cell viability, promoted cell apoptotic rate, and down-regulated the expression of miR-431 in human cardiomyocytes. The down-regulation of miR-431 by its inhibitor reduced cell viability and induced cell apoptosis in the human cardiomyocytes. Moreover, miR-431 down-regulated the expression of autophagy-related 3 (ATG3) via targeting the 3ʹ-untranslated region of ATG3. Up-regulated expression of ATG3 by pcDNA3.1-ATG3 reversed the protective role of the overexpression of miR-431 on cell viability and cell apoptosis in H/R-treated human cardiomyocytes. More importantly, H/R treatments promoted autophagy in the human cardiomyocytes, and this effect was greatly alleviated via miR-431-mimic transfection. Our results suggested that miR-431 overexpression attenuated the H/R-induced myocardial damage at least partly through regulating the expression of ATG3.

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Abstract 13879: Ischemic Postconditioning Confers Cardioprotection through Adiponectin-dependent Mitochondrial STAT3 Activation in Mice

Circulation ◽

10.1161/circ.130.suppl_2.13879 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Haobo Li ◽

Michael G Irwin ◽

Zhengyuan Xia

Keyword(s):

Cell Injury ◽

Troponin I ◽

Ischemia Reperfusion Injury ◽

Apoptotic Cell ◽

Ischemia Reperfusion ◽

Cardiac Injury ◽

Systolic Pressure ◽

Gene Knockdown ◽

Area At Risk ◽

In Cells

Introduction: Signal transducer and activator of transcription 3 (STAT3) plays a key role in postconditioning (IPo) mediated protection against myocardial ischemia reperfusion injury, but the mechanism by which IPo activates STAT3 is unknown. Adiponectin (APN), a protein with anti-ischemic properties, activates STAT3. We hypothesized that IPo activates mitochondrial STAT3 (MitoSTAT3) via APN signaling. Methods and Results: Wild type (WT) and APN knockout (KO) mice were either sham operated or subjected to 30 min of coronary artery occlusion followed by 2 hours of reperfusion with or without IPo (3 cycles of 10 seconds reperfusion and 10 seconds reocclusion; n=8/group). At the end of reperfusion, KO mice exhibited more severe myocardial injury evidenced as increased infarct size (% of area at risk) 49.2±2.0 vs WT 39.4±3.5, P <0.01; plasma troponin I (ng/ml): KO 72.8±7.6 vs WT 45.7±4.0, P <0.01; worse cardiac function (lower dP/dt max and end-systolic pressure-volume relation, P <0.05); more severely impaired mitochondrial function (reductions in complex IV and complex V protein expression) and more severe reduction of MitoSTAT3 phosphorylation (activation) at site Ser727, P <0.01. IPo significantly attenuated post-ischemic cardiac injury and dysfunction with a concomitant increase in phosphorylated MitoSTAT3 and attenuation of mitochondrial dysfunction in WT (all P <0.05) but not in KO mice. In cultured cardiac H9C2 cells, hypoxic postconditioning (HPo, 3 cycles of 5 min hypoxia and 5 min reoxygenation) significantly attenuated hypoxia/reoxygenation (HR, 3 hours hypoxia/3 hours reoxygenation) induced cell injury (increased apoptotic cell death as % of HR): HR 100.2±0.4 vs HPo 78.2±4.8, P <0.05) and reduced mitochondrial transmembrane potential (% total cells, HR 37.2±4.9 vs HPo 23.5±3.7, P <0.01). APN, adiponectin receptor 1 (AdipoR1), or STAT3 gene knockdown but not AdipoR2 gene knockdown, respectively, abolished HPo cellular protection (all P <0.05 vs. HPo). APN supplementation (10μg/ml) restored HPo protection in cells with APN knockdown but not in cells with AdipoR1or STAT3 gene knockdown. Conclusion: Adiponectin and AdipoR1 signaling are required for IPo to activate myocardial mitochondrial STAT3 to confer cardioprotection.

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Abstract 212: Cd4+ T-cell Activation By T-cell Receptor Engagement Contributes To Myocardial Ischemia-reperfusion Injury

Circulation Research ◽

10.1161/res.113.suppl_1.a212 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Ulrich Hofmann ◽

Denise Mathes ◽

Johannes Weirather ◽

Niklas Beyersdorf ◽

Thomas Kerkau ◽

...

Keyword(s):

At Risk ◽

T Cells ◽

T Cell ◽

Infarct Size ◽

T Cell Receptor ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Cell Receptor ◽

Area At Risk ◽

Infarct Area

Background: We have recently shown that CD4 + but not CD8 + T-cells contribute to ischemia-reperfusion injury of the myocardium. We therefore hypothesized that CD4 + T-cells become activated by autoantigen recognition via their T-cell receptor during reperfusion. Methods and Results: Infarct size as percent of the area-at-risk was determined by combined Evans` blue and triphenyltetrazolium (TTC) staining after 30 minutes of in vivo ischemia followed by 24 hours reperfusion in mice. After 24 hours of reperfusion there was a significantly increased population of CD4 + T-cells which expressed the surface protein CD40L in comparison to sham operated mice [n≥7; p<0.05; WT 10.8 ± 0.2% vs. sham 6.4 ± 0.5%]. CD40L is typically expressed in T-cells activated by T-cell receptor engagement. OT-II mice carry a transgenic T-cell receptor with specificity for an ovalbumin-derived peptide. These mice have a limited T-cell receptor repertoire, dominated by specificity for the irrelevant antigen ovalbumin. After 30 minutes of ischemia and 24 hours of reperfusion OT-II mice showed significantly reduction in infarct size [n≥4; p= 0.02; infarct/area at risk: OTII mice 38.9 ± 2.4% vs. WT mice 63.7 ± 6.6 % ]. Administration of a CD40L blocking antibody to wildtype mice also reduced infarct size when compared to administration of isotype-matched antibodies [n≥6; p = 0.03; infarct/ area at risk: anti-CD154 treatment 60.4 ± 3.4% vs. control 75.3 ± 4.1%]. CD4 + CD25 + Foxp3 + T-cells (natural T-regulatory cells) have a low activation threshold and constitute a T-cell subset with reactivity against autoantigens. Depletion of these cells by diphtheria-toxin application in a mouse model expressing the diphtheria-toxin receptor under the Foxp3 promotor also resulted in a significant reduction of infarct size when compared to diphtheria-toxin treated wildtype mice [n≥4; p=0.03; infarct/ area at risk: T reg -depleted DEREG mice 51.9± 3% vs. WT littermates 72.3± 2%]. Conclusion: Our results indicate that CD4 + T-cells that have been activated by an MHC class II/ T-cell receptor dependent mechanism, presumably by autoantigen recognition, contribute to myocardial ischemia-reperfusion injury.

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Abstract 300: Topical Application of IcyHot Reduces Myocardial Infarct Size in Rodents by a TRPA1-dependent Mechanism

Circulation Research ◽

10.1161/res.121.suppl_1.300 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Yun Wu ◽

Yao Lu ◽

Eric R Gross

Keyword(s):

Infarct Size ◽

Transient Receptor Potential ◽

Ischemia Reperfusion Injury ◽

Calcium Influx ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Myocardial Infarct Size ◽

Sprague Dawley ◽

Area At Risk ◽

Reactive Aldehydes

Toxic reactive aldehydes are formed during ischemia-reperfusion. The ion channel transient receptor potential ankryin 1 (TRPA1) is irreversibly modified by reactive aldehydes which can cause calcium influx and cell death. Here we tested whether topically applied creams containing a reversible TRPA1 agonist could reduce myocardial infarct size. Male Sprague-Dawley rats 8-10 weeks age were subjected to an in vivo myocardial ischemia-reperfusion model of 30 minutes of left anterior descending (LAD) coronary artery ischemia followed by 2 hours reperfusion. Prior to ischemia, rats were untreated or had 1g of cream applied to the abdomen. The creams tested were IcyHot, Bengay, Tiger Balm, or preparation H (Fig. 1A). Hearts were negatively stained for the area at risk and the infarct size was determined by using TTC staining (Fig. 1B). A subset of rodents prior to receiving IcyHot also received an intravenous bolus of the TRPA1 antagonist TCS-5861528 (1mg/kg) or AP-18 (1mg/kg). Interestingly, both IcyHot and Bengay reduced myocardial infarct size compared to untreated rodents (Fig. 1C and 1D IcyHot: 41±3%*, Bengay: 50±2%* versus control 62±1%, n=6/group, *P<0.001). Both preparation H and Tiger Balm failed to reduce myocardial infarct size (Tiger Balm: 63±2%, preparation H 59±2%). Giving a TRPA1 antagonist prior to IcyHot also blocked the reduction in infarct size. Our additional data also indicates the methyl salicylate (mint) in IcyHot and Bengay is the agent that limits myocardial infarct size. Since IcyHot and Bengay are safely used by humans, targeting TRPA1 by using products such as these could be quickly translatable and widely used to reduce ischemia-reperfusion injury.

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Abstract 1008: A Protective Role for Cardiac Specific Muscle Ring Finger-1 (MuRF1) in Ischemia/Reperfusion Injury In Vivo

Circulation ◽

10.1161/circ.116.suppl_16.ii_200-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Monte S Willis ◽

Mauricio Rojas ◽

Pamela Lockyer ◽

Thomas G Hampton ◽

Luge Li ◽

...

Keyword(s):

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Critical Role ◽

Ring Finger ◽

Left Ventricular ◽

Ex Situ ◽

Histological Evaluation ◽

Area At Risk ◽

Fractional Shortening

We previously identified a critical role for MuRF1 in suppressing pathologic cardiac hypertrophy. To extend these observations to other pathologic processes, we tested the role of MuRF1 in cardiac ischemia reperfusion (I/R) injury. We challenged MuRF1 transgenic (Tg) mice to I/R injury both ex situ and in vivo. First, we examined isolated MuRF1 Tg and age-matched sibling wild-type (WT) hearts after global ischemia (15 min) followed by reperfusion (20 min) in a Langendorff apparatus. Baseline function of MuRF1 Tg hearts did not significantly differ from WT hearts (mean left ventricular developed pressure (LVDP) 88.5 +/− 18 vs. 82.5 +/− 6.7, respectively; n = 4/group). Mean LVDP of hearts from MuRF1 Tg mice after reperfusion was 76.0 +/− 22.9% of baseline function compared to 27.2 +/− 13.3% in WT hearts (N = 5/group, P< 0.05)). To confirm that MuRF1 is cardioprotective in vivo, we subjected MuRF1 Tg and WT mice to a 30 minute ligation of the left anterior descending coronary artery, followed by 24 hours reperfusion. Mice underwent conscious echocardiography at baseline and after 24 hours; cardiac function was further interrogated by Millar pressure volume catheterization at 24 hours. Additionally, hearts underwent a histological evaluation of area at risk and infarct size. By echocardiography, a ~7% decrease in fractional shortening was identified in MuRF1 Tg mice after 24 hours reperfusion compared to baseline. This was in striking contrast to WT mice, which exhibited ~48% decrease in fractional shortening. Steady state catheterization measurements showed a significantly higher ejection fraction in MuRF1 Tg compared to WT mice after I/R injury (81.6 ± 2.3% vs. 49.0 +/− 4.0%, P < 0.05). Contractility reflected by +dP/dt max was better preserved in MuRF1 Tg compared to WT mice after I/R injury (12,614 +/− 776 vs. 7,448 +/−752, N = 3–12/group, P < 0.05). Histologically, the area of infarct in MuRF1 Tg mice was significantly smaller (10.0 +/− 0.8%) than in WT mice (25.5 +/− 2.5%, N = 4/group, P < 0.05). We demonstrate here for the first time that cardiac MuRF1 expression preserves function after I/R injury in vivo. Since MuRF1 is known to interact with metabolic and structural targets, this model will allow us to identify mechanisms by which MuRF1 modifies cardiac pathophysiology.

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Abstract 552: Bradykinin Receptor B1/ Matrix Metalloprotease 3 Pathway is a Novel Target in Preventing Cardiac Ischemia-reperfusion Injury

Circulation Research ◽

10.1161/res.127.suppl_1.552 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Qin Zhang ◽

Lizhuo Ai ◽

Lifeng Liu ◽

Cristian Betancourt ◽

Maura Knapp ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Endothelial Barrier ◽

Matrix Metalloprotease ◽

Barrier Dysfunction ◽

Area At Risk ◽

Bradykinin Receptor

Introduction: Impaired endothelial function leads to the progression of heart failure after Ischemia-reperfusion (IR). Kinin activation of bradykinin receptor 1 (B1R), a G protein-coupled receptor that has been found to induce capillary leakage, may serve as a critical mediator in cardiac microvascular barrier dysfunction. However, the underlying mechanisms are not clear. We found that B1R inhibition abolished IR-induced endothelial matrix metalloprotease (MMP3) expression and improved endothelial barrier formation. Thus, we hypothesized that B1R antagonist protects against cardiac IR injury through an MMP3 pathway. Methods and Results: MMP3-/- mice and their littermate controls (WT) were subjected to either cardiac IR or sham control. The baseline characteristics of these mice showed minimal phenotypes. Cardiac function was determined at 3, 7 and 24 days post-IR by echocardiography. The MMP3-/- mice displayed improved cardiac function compared to the control mice, as determined by fractional shortening (26% ± 1.1 MMP3-/- vs. 21% ± 0.9 WT, p<0.05, n=5) and ejection fraction (48% ± 1.9 MMP3-/- vs. 42% ± 2.8.1 WT, p<0.05, n=5), and treating with B1R antagonist (300 μg/Kg) significantly reduced serum MMP3 levels (p<0.01). Compared to the control mice, MMP3-/- mice had significantly less infarction/area at risk 24 hours post-IR demonstrated through TTC staining. In vitro studies revealed that cellular hypoxia-reoxygenation (HR) injury significantly increased both B1R and MMP3 expression levels in primary isolated cardiac mice microvascular endothelial cells (mCMVEC). MMP3 levels were measured via ELISA. Moreover, B1R agonist treatment (1uM) increased MMP3 levels, while the use of the antagonist attenuated the increase of MMP3 in response to HR. Finally, the use of B1R antagonist improved MMP3 induced endothelial barrier dysfunction, which was measured by the electric cell-substrate impedance sensing (ECIS) system. Taken together, the results demonstrated that B1R antagonist abolished IR induced MMP3 induction and that the deletion of MMP3 is protective of cardiac function upon IR injury. Conclusions: MMP3 is a critical regulator of cardiac microvascular barrier function, and B1R/MMP3 could potentially serve as a novel therapeutic target for heart failure in response to IR injury.

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Inhibition of Myocardial Ischemia/Reperfusion Injury by Exosomes Secreted from Mesenchymal Stem Cells

Stem Cells International ◽

10.1155/2016/4328362 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 18

Author(s):

Heng Zhang ◽

Meng Xiang ◽

Dan Meng ◽

Ning Sun ◽

Sifeng Chen

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Left Ventricle ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Therapeutic Potential ◽

Heart Function ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Area At Risk

Exosomes secreted by mesenchymal stem cells have shown great therapeutic potential in regenerative medicine. In this study, we performed meta-analysis to assess the clinical effectiveness of using exosomes in ischemia/reperfusion injury based on the reports published between January 2000 and September 2015 and indexed in the PUBMED and Web of Science databases. The effect of exosomes on heart function was evaluated according to the following parameters: the area at risk as a percentage of the left ventricle, infarct size as a percentage of the area at risk, infarct size as a percentage of the left ventricle, left ventricular ejection fraction, left ventricular fraction shortening, end-diastolic volume, and end-systolic volume. Our analysis indicated that the currently available evidence confirmed the therapeutic potential of mesenchymal stem cell-secreted exosomes in the improvement of heart function. However, further mechanistic studies, therapeutic safety, and clinical trials are required for optimization and validation of this approach to cardiac regeneration after ischemia/reperfusion injury.

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Diazoxide Protects against Myocardial Ischemia/Reperfusion Injury by Moderating ERS via Regulation of the miR-10a/IRE1 Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/4957238 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16

Author(s):

Lin Zhang ◽

Shuang Cai ◽

Song Cao ◽

Jia Nie ◽

Wenjing Zhou ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Heart Disease ◽

Protective Effect ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Reperfusion Therapy ◽

Potassium Channel Opener ◽

Myocardial Ischemia Reperfusion Injury ◽

Myocardial Ischemia Reperfusion

Nowadays, reperfusion is still the most effective treatment for ischemic heart disease. However, cardiac reperfusion therapy would lead to reperfusion injury, which may have resulted from endoplasmic reticulum stress (ERS) during reperfusion. Diazoxide (DZ) is a highly selective mitochondrial adenosine triphosphate-sensitive potassium channel opener. Its protective effect on I/R injury has been confirmed in many organs such as the heart and brain. However, the mechanism of its protective effect has not been fully elucidated. MicroRNAs (miRNAs) are widely involved in pathologies of heart disease. In this study, we found that miR-10a expression was highly upregulated in the myocardial I/R groups, and DZ treatment significantly reduced the expression of miR-10a. More importantly, we found that DZ treatment can moderate ERS via regulation of the miR-10a/IRE1 pathway in the I/R and H/R models, thereby protecting myocardial H/R injury.

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