1002-101 Pyrroloquinoline quinone decreases myocardial infarct size and improves cardiac function in rat models of ischemia and ischemia-reperfusion

Background/Aims: Epoxyeicosatrienoic acids (EETs) are cytochrome P450 epoxygenase (CYP) metabolites of arachidonic acid and have multiple cardiovascular effects. Ophiopogonin D (OP-D) is an important effective monomeric component in Shenmai injection (SM-I). Both have been reported to have a variety of biological functions, including anti-inflammatory, anti-oxidant, and anti-apoptotic effects. We previously demonstrated that OP-D–mediated cardioprotection involves activation of CYP2J2/3 and enhancement of circulating EETs levels in vitro and can be developed as a novel drug for the therapy of myocardial ischemia-reperfusion (MI/R) injury. We therefore hypothesized that the protective effects of OP-D and SM-I against MI/R injury are associated with increased expression of CYP2J3 and enhanced circulating 11,12-EET levels in vivo. Methods: A rat model of MI/R injury was generated by ligation of the left anterior descending coronary artery for 40 min, followed by reperfusion for 2 h to determine the protective effects and potential mechanisms of OP-D and SM-I. Electrocardiogram and ultrasonic cardiogram were used to evaluate cardiac function; 2,3,5-triphenyltetrazolium chloride was used to measure myocardial infarct size; hematoxylin and eosin staining and transmission electron microscopy were used to observe the morphology of myocardial tissue; and the expression of related proteins in the mechanistic study was observed by western blot analysis. Results: We found that OP-D and SM-I exert protective effects on MI/R injury, including regulation of cardiac function, reduction of lactate dehydrogenase and creatine kinase production, attenuation of myocardial infarct size, and improvement of the recovery of damaged myocardial structures. We found that OP-D and SM-I activate CYP2J3 expression and increase levels of circulating 11,12-EET in MI/R-injured rats. Conclusion: We tested the hypothesis that the cardioprotective effects of OP-D and SM-I on MI/R injury are associated with increased expression of CYP2J3 and enhanced circulating 11,12-EET levels in rats. Taken together, our results show that the effects of OP-D and SM-I were also mediated by the activation of the PI3K/Akt/eNOS signaling pathway, while inhibition of the NF-κB signaling pathway and antioxidant and anti-apoptotic effects were involved in the cardioprotective effects of OP-D and SM-I.

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Inhibiting miR-205 Alleviates Cardiac Ischemia/Reperfusion Injury by Regulating Oxidative Stress, Mitochondrial Function, and Apoptosis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/9986506 ◽

2021 ◽

Vol 2021 ◽

pp. 1-17

Author(s):

Yuerong Xu ◽

Wangang Guo ◽

Di Zeng ◽

Yexian Fang ◽

Runze Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Function ◽

Infarct Size ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Cardiac Ischemia ◽

Myocardial Infarct Size ◽

Neonatal Cardiomyocytes

Background. miR-205 is important for oxidative stress, mitochondrial dysfunction, and apoptosis. The roles of miR-205 in cardiac ischemia/reperfusion (I/R) injury remain unknown. The aim of this research is to reveal whether miR-205 could regulate cardiac I/R injury by focusing upon the oxidative stress, mitochondrial function, and apoptosis. Methods. Levels of miR-205 and Rnd3 were examined in the hearts with I/R injury. Myocardial infarct size, cardiac function, oxidative stress, mitochondria function, and cardiomyocyte apoptosis were detected in mice with myocardial ischemia/reperfusion (MI/R) injury. The primary neonatal cardiomyocytes underwent hypoxia/reoxygenation (H/R) to simulate MI/R injury. Results. miR-205 levels were significantly elevated in cardiac tissues from I/R in comparison with those from Sham. In comparison with controls, levels of Rnd3 were significantly decreased in the hearts from mice with MI/R injury. Furthermore, inhibiting miR-205 alleviated MI/R-induced apoptosis, reduced infarct size, prevented oxidative stress increase and mitochondrial fragmentation, and improved mitochondrial functional capacity and cardiac function. Consistently, overexpression of miR-205 increased infarct size and promoted apoptosis, oxidative stress, and mitochondrial dysfunction in mice with MI/R injury. In cultured mouse neonatal cardiomyocytes, downregulation of miR-205 reduced oxidative stress in H/R-treated cardiomyocytes. Finally, inhibiting Rnd3 ablated the cardioprotective effects of miR-205 inhibitor in MI/R injury. Conclusions. We conclude that inhibiting miR-205 reduces infarct size, improves cardiac function, and suppresses oxidative stress, mitochondrial dysfunction, and apoptosis by promoting Rnd3 in MI/R injury. miR-205 inhibitor-induced Rnd3 activation is a valid target to treat MI/R injury.

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EFFECTS OF EXERCISE COMBINED WITH APELIN-13 ON CARDIAC FUNCTION IN THE ISOLATED RAT HEART

Revista Brasileira de Medicina do Esporte ◽

10.1590/1517-869220182404175002 ◽

2018 ◽

Vol 24 (4) ◽

pp. 273-279

Author(s):

Afshin Nazari ◽

Khadige Zahabi ◽

Yaser Azizi ◽

Maryam Moghimian

Keyword(s):

Exercise Training ◽

Cardiac Function ◽

Infarct Size ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Combined Treatment ◽

Left Ventricular ◽

Male Rats ◽

Myocardial Infarct Size ◽

Creatine Kinase Mb

ABSTRACT Exercise and apelin have been shown to increase cardiac function and elicit tolerance to ischemia/reperfusion (IR) injuries. This study aimed at determining whether the combination of exercise training and apelin pretreatment could integrate the protective effects of each of them in the heart against IR injury. Male rats were divided into four experimental groups: 1: Rats with ischemia/reperfusion (IR), 2: subjected to exercise training for 8 weeks (EX+IR), 3: apelin-13 (10 nmol/kg/day) for 7 days (Apel+IR) in the last week of training, and 4: exercise training plus apelin-13 (EX+Apel+IR). Isolated hearts were perfused using the Langendorff method and subjected to 30 min of regional ischemia followed by 60 min of reperfusion. Treadmill exercise training was conducted for 8 weeks. Hemodynamic parameters were recorded throughout the experiment. Ischemia-induced arrhythmias, myocardial infarct size (IS), creatine kinase-MB (CK-MB) isoenzyme and plasma lactate dehydrogenase (LDH) activity was measured in all animals. Administration of apelin-13 plus exercise increased left ventricular developed pressure (LVDP) at the end of ischemia and reperfusion compared with other groups. After 30 min of ischemia, dP/dtmax was higher in EX+Apel+IR than in Apel+IR and EX+IR groups. During 30 min ischemia, exercise training, apelin-13 and combined treatment produced a significant reduction in the numbers of premature ventricular complexes. A combination of exercise and apelin-13 also reduced infarct size, CK-MB, LDH and severity of arrhythmia. These results suggest that combined therapies with apelin-13 and exercise training may integrate the beneficial effects of each of them alone on cardiac contractility, arrhythmia and limiting of infarct size. Level of evidence I; Therapeutic Studies - Investigating the Results of Treatment.

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DIDS Reduces Ischemia/Reperfusion-Induced Myocardial Injury in Rats

Cellular Physiology and Biochemistry ◽

10.1159/000369728 ◽

2015 ◽

Vol 35 (2) ◽

pp. 676-688 ◽

Cited By ~ 17

Author(s):

Xiaoming Wang ◽

Yanan Cao ◽

Mingzhi Shen ◽

Bo Wang ◽

Weiwei Zhang ◽

...

Keyword(s):

Cardiac Function ◽

Infarct Size ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Disulfonic Acid ◽

Myocardial Infarct Size ◽

Ros Production ◽

Akt Phosphorylation ◽

Micro Pump

Background/Aims: Anion channels such as chloride channel are known to participate in the regulation of a wide variety of cellular processes including development, differentiation, proliferation, apoptosis and regeneration. This study was designed to examine the effect of the non-selective anion channel blocker 4,4'-Diisothiocyanostilbene-2, 2'-disulfonic acid (DIDS) on cardiac function and apoptosis using a rat model of ischemia/reperfusion (I/R). Methods: Fifty male SD rats were randomly divided into the following groups including sham, I/R and I/R+DIDS (7, 14 or 28 mg/kg). In DIDS group, rats received DIDS treatment (4 ml/kg/hr) at the beginning of reperfusion for 2 hrs using a programmed micro-pump. Cardiac function was evaluated including left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP) as well as positive and negative maximal derivatives of left ventricular pressure (± dP/dtmax). Myocardial infarct size was detected using the double staining with 2, 3, 5-triphenyl-2H-tetra-zolium chloride (TTC) and Evan's blue dye. DNA ladder, TUNEL assay, Bax and Bcl-2 protein levels were evaluated. Levels of ROS and Akt phosphorylation were detected. Results: I/R injury compromised cardiac function as manifested by reduced LVSP and ± dP/dtmax as well as pronounced apoptosis. I/R-induced cardiac anomalies were markedly ameliorated by DIDS. DIDS retarded I/R-induced myocardial infarct and apoptosis. In addition, DIDS ameliorated I/R-induced ROS production and Akt dephosphorylation in the heart. Conclusion: Taken together, our data revealed that DIDS may protect cardiomyocytes against I/R injury as evidenced by improved cardiac function, Bcl-2, Akt phosphorylation, and reduced myocardial apoptosis, Bax expression, ROS production and myocardial infarct size.

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Faculty Opinions recommendation of Vardenafil: a novel type 5 phosphodiesterase inhibitor reduces myocardial infarct size following ischemia/reperfusion injury via opening of mitochondrial K(ATP) channels in rabbits.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1008695.372854 ◽

2006 ◽

Author(s):

Andreas Deussen

Keyword(s):

Infarct Size ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Phosphodiesterase Inhibitor ◽

Myocardial Infarct Size

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Cardioprotection with esmolol-based cardioplegia for non-infarcted and infarcted rat hearts

European Journal of Cardio-Thoracic Surgery ◽

10.1093/ejcts/ezab117 ◽

2021 ◽

Author(s):

Alexander B Veitinger ◽

Audrey Komguem ◽

Lena Assling-Simon ◽

Martina Heep ◽

Julia Schipke ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Infarct Size ◽

Myocardial Infarct ◽

Lactate Production ◽

Left Ventricular ◽

Myocardial Infarct Size ◽

Cardioplegic Arrest ◽

Blood Cardioplegia ◽

Rat Hearts

Abstract OBJECTIVES Esmolol-based cardioplegic arrest offers better cardioprotection than crystalloid cardioplegia but has been compared experimentally with blood cardioplegia only once. We investigated the influence of esmolol crystalloid cardioplegia (ECCP), esmolol blood cardioplegia (EBCP) and Calafiore blood cardioplegia (Cala) on cardiac function, metabolism and infarct size in non-infarcted and infarcted isolated rat hearts. METHODS Two studies were performed: (i) the hearts were subjected to a 90-min cardioplegic arrest with ECCP, EBCP or Cala and (ii) a regional myocardial infarction was created 30 min before a 90-min cardioplegic arrest. Left ventricular peak developed pressure (LVpdP), velocity of contractility (dLVP/dtmax), velocity of relaxation over time (dLVP/dtmin), heart rate and coronary flow were recorded. In addition, the metabolic parameters were analysed. The infarct size was determined by planimetry, and the myocardial damage was determined by electron microscopy. RESULTS In non-infarcted hearts, cardiac function was better preserved with ECCP than with EBCP or Cala relative to baseline values (LVpdP: 100 ± 28% vs 86 ± 11% vs 57 ± 7%; P = 0.002). Infarcted hearts showed similar haemodynamic recovery for ECCP, EBCP and Cala (LVpdP: 85 ± 46% vs 89 ± 55% vs 56 ± 26%; P = 0.30). The lactate production with EBCP was lower than with ECCP (0.6 ± 0.7 vs 1.4 ± 0.5 μmol/min; P = 0.017). The myocardial infarct size and (ECCP vs EBCP vs Cala: 16 ± 7% vs 15 ± 9% vs 24 ± 13%; P = 0.21) the ultrastructural preservation was similar in all groups. CONCLUSIONS In non-infarcted rat hearts, esmolol-based cardioplegia, particularly ECCP, offers better myocardial protection than Calafiore. After an acute myocardial infarction, cardioprotection with esmolol-based cardioplegia is similar to that with Calafiore.

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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 2894: Essential Role of ERK 1/2 in Sildenafil-Induced Early and Delayed Cardioprotection in Mice

Circulation ◽

10.1161/circ.118.suppl_18.s_794-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Anindita das ◽

Lei Xi ◽

Fadi N Salloum ◽

Yuan J Rao ◽

Rakesh C Kukreja

Keyword(s):

South Carolina ◽

Infarct Size ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Critical Role ◽

Heart Association ◽

Myocardial Infarct Size ◽

Western Blots ◽

Delayed Cardioprotection

Background: Sildenafil (SIL), a potent inhibitor of phosphodiesterase-5 induces powerful protection against myocardial ischemia-reperfusion (I-R) injury through activation of protein kinase G (PKG). However, the downstream targets of PKG in SIL-induced cardioprotection remain unclear. We hypothesized that PKG-dependent activation of survival kinase, ERK may play a critical role in SIL-induced cardioprotection in mice. Methods & Results: Ventricular myocytes were isolated from adult male ICR mice and exposed to 40 min of simulated ischemia (SI) with/without 1 hr pre-incubation of SIL (1 μM). Myocyte necrosis and apoptosis were determined after 1 hr or 18 hrs of reoxygenation (RO) using trypan blue or TUNEL assay, respectively. Pretreatment with SIL protected cardiomyocytes after SI-RO (necrosis 18.5±0.5% and apoptosis 6.6±0.7%; n=4, p<0.001) as compared with controls (necrosis 42.1±1.8% and apoptosis 23.3±0.9%). Co-incubation of PD98059 (20 μM), a selective ERK1/2 inhibitor blocked both anti-necrotic and anti-apoptotic protection in cardiomyocytes. Furthermore, intra-coronary infusion of SIL (1 μM) in Langendorff isolated mouse hearts 10 min prior to zero-flow global I (20 min) and R (30 min) significantly reduced myocardial infarct size (from 29.4±2.4% to 16.0±3.0%; p<0.05, n=6). Co-treatment of PD98059 abrogated SIL-induced protection (33.0±5.9; n=4). To evaluate the role of ERK1/2 in delayed cardioprotection, mice were treated with saline or SIL (0.7 mg/kg i.p.) 24 hours before global I-R in Langendorff mode. PD98059 (1 mg/kg) was administered (i.p.) 30 min before the treatment of SIL. Infarct size was reduced from 27.6±3.3% in saline-treated controls to 6.9±1.2% in SIL-treated mice (P<0.05, n=6). The delayed protective effect of SIL was also abolished by PD98059 (22.5±2.3%). Western Blots revealed that SIL significantly increased phosphorylation of ERK1/2 which was blocked by PKG inhibitor, KT5823 in the heart and adult myocytes. Selective knockdown of PKG in cardiomyocytes with short hairpin RNA of PKG also blocked the phosphorylation of ERK1/2. Conclusion: SIL-induced cardioprotection involves the activation and phosphorylation of ERK which appear to be intimately linked with a PKG-dependent survival pathway. This research has received full or partial funding support from the American Heart Association, AHA Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia & Washington, DC).

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