Remote Limb Ischaemic Postconditioning Protects Against Myocardial Ischaemia/Reperfusion Injury in Mice: Activation of JAK/STAT3-Mediated Nrf2-Antioxidant Signalling

Background: This study aimed to evaluate the protective effect and mechanisms of remote limb ischaemic postconditioning (RIPostC) against myocardial ischaemia/reperfusion (IR) injury. Methods: Male mice underwent 45 min of coronary artery occlusion followed by 2 h of reperfusion. RIPostC was achieved by three cycles of 5 min of ischaemia and 5 min of reperfusion in the left hind limb at the start of the reperfusion period. After 2 h of cardiac reperfusion, myocardial infarct size, cardiac enzyme release, apoptosis and oxidative stress were assessed. Protein expression and phosphorylation were measured by Western blotting. Results: RIPostC significantly decreased cardiac IR injury, as reflected by reduced infarct size and cellular apoptosis (22.9 ± 3.3% vs 40.9 ± 6.2% and 13.4% ± 3.1% vs 26.2% ± 3.1%, respectively, both P < 0.01) as well as plasma creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) release (21.97 ± 4.08 vs 35.86 ± 2.91 ng/ml and 6.17 ± 0.58 vs 8.37 ± 0.89 U/ml, respectively, both P < 0.01) compared with the IR group. RIPostC significantly increased the phosphorylation of myocardial STAT3, Akt and eNOS (P < 0.01). In addition, RIPostC elevated the nuclear translocation of Nrf2 and the expression of HO-1 and reduced myocardial oxidative stress (P < 0.05). Interestingly, pretreatment with the JAK/STAT3 inhibitor AG490 blocked the cardioprotective effect of RIPostC accompanied by decreased phosphorylation of myocardial STAT3, Akt and eNOS (P < 0.05), decreased nuclear translocation of Nrf2 and expression of HO-1, as well as increased oxidative stress (P < 0.05). Conclusion: RIPostC attenuates apoptosis and protects against myocardial IR injury, possibly through the activation of JAK/STAT3-mediated Nrf2-antioxidant signalling.

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Hydralazine protects the heart against acute ischaemia/reperfusion injury by inhibiting Drp1-mediated mitochondrial fission

Cardiovascular Research ◽

10.1093/cvr/cvaa343 ◽

2021 ◽

Author(s):

Siavash Beikoghli Kalkhoran ◽

Janos Kriston-Vizi ◽

Sauri Hernandez-Resendiz ◽

Gustavo E Crespo-Avilan ◽

Ayeshah A Rosdah ◽

...

Keyword(s):

Oxidative Stress ◽

Infarct Size ◽

Myocardial Infarct ◽

Mitochondrial Fission ◽

Vehicle Control ◽

Myocardial Infarct Size ◽

Ischaemia Reperfusion Injury ◽

Ischaemia Reperfusion ◽

Pre Treatment ◽

Apoptotic Effects

Abstract Aims Genetic and pharmacological inhibition of mitochondrial fission induced by acute myocardial ischaemia/reperfusion injury (IRI) has been shown to reduce myocardial infarct size. The clinically used anti-hypertensive and heart failure medication, hydralazine, is known to have anti-oxidant and anti-apoptotic effects. Here, we investigated whether hydralazine confers acute cardioprotection by inhibiting Drp1-mediated mitochondrial fission. Methods and results Pre-treatment with hydralazine was shown to inhibit both mitochondrial fission and mitochondrial membrane depolarisation induced by oxidative stress in HeLa cells. In mouse embryonic fibroblasts (MEFs), pre-treatment with hydralazine attenuated mitochondrial fission and cell death induced by oxidative stress, but this effect was absent in MEFs deficient in the mitochondrial fission protein, Drp1. Molecular docking and surface plasmon resonance studies demonstrated binding of hydralazine to the GTPase domain of the mitochondrial fission protein, Drp1 (KD 8.6±1.0 µM), and inhibition of Drp1 GTPase activity in a dose-dependent manner. In isolated adult murine cardiomyocytes subjected to simulated IRI, hydralazine inhibited mitochondrial fission, preserved mitochondrial fusion events, and reduced cardiomyocyte death (hydralazine 24.7±2.5% vs. control 34.1±1.5%, P=0.0012). In ex vivo perfused murine hearts subjected to acute IRI, pre-treatment with hydralazine reduced myocardial infarct size (as % left ventricle: hydralazine 29.6±6.5% vs. vehicle control 54.1±4.9%, P=0.0083), and in the murine heart subjected to in vivo IRI, the administration of hydralazine at reperfusion, decreased myocardial infarct size (as % area-at-risk: hydralazine 28.9±3.0% vs. vehicle control 58.2±3.8%, P<0.001). Conclusion We show that, in addition to its antioxidant and anti-apoptotic effects, hydralazine, confers acute cardioprotection by inhibiting IRI-induced mitochondrial fission, raising the possibility of repurposing hydralazine as a novel cardioprotective therapy for improving post-infarction outcomes.

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Cardioprotective Effect of the Aqueous Extract of Lavender Flower against Myocardial Ischemia/Reperfusion Injury

Journal of Chemistry ◽

10.1155/2014/368376 ◽

2014 ◽

Vol 2014 ◽

pp. 1-6 ◽

Cited By ~ 2

Author(s):

Dong Wang ◽

Xin Guo ◽

Mingjie Zhou ◽

Jichun Han ◽

Bo Han ◽

...

Keyword(s):

Oxidative Stress ◽

Myocardial Ischemia ◽

Infarct Size ◽

Aqueous Extract ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Myocardial Infarct Size ◽

Myocardial Oxidative Stress ◽

Myocardial Ischemia Reperfusion

This study was conducted to evaluate the cardioprotective property of the aqueous extract of lavender flower (LFAE). The myocardial ischemia/reperfusion (I/R) injury of rat was prepared by Langendorff retrograde perfusion technology. The heart was preperfused with K-H solution containing LFAE for 10 min before 20 minutes global ischemia, and then the reperfusion with K-H solution was conducted for 45 min. The left ventricular developed pressure (LVDP) and the maximum up/downrate of left ventricular pressure (±dp/dtmax) were recorded by physiological recorder as the myocardial function and the myocardial infarct size was detected by TTC staining. Lactate dehydrogenase (LDH) and creatine kinase (CK) activities in the effluent were measured to determine the myocardial injury degree. The superoxide anion dismutase (SOD) and malondialdehyde (MDA) in myocardial tissue were detected to determine the oxidative stress degree. The results showed that the pretreatment with LFAE significantly decreased the myocardial infarct size and also decreased the LDH, CK activities, and MDA level, while it increased the LVDP, ±dp/dtmax, SOD activities, and the coronary artery flow. Our findings indicated that LFAE could provide protection for heart against the I/R injury which may be related to the improvement of myocardial oxidative stress states.

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Reduction of myocardial leukocyte accumulation and myocardial infarct size following administration of BAY u3405, a thromboxane A2 receptor antagonist, in myocardial ischaemia-reperfusion injury

Agents and Actions ◽

10.1007/bf01998967 ◽

1993 ◽

Vol 39 (3-4) ◽

pp. 143-149 ◽

Cited By ~ 4

Author(s):

F. Squadrito ◽

M. Ioculano ◽

D. Altavilla ◽

B. Zingarelli ◽

P. Canale ◽

...

Keyword(s):

Infarct Size ◽

Receptor Antagonist ◽

Myocardial Ischaemia ◽

Myocardial Infarct ◽

Thromboxane A2 ◽

Myocardial Infarct Size ◽

Ischaemia Reperfusion Injury ◽

Thromboxane A2 Receptor ◽

Leukocyte Accumulation ◽

Ischaemia Reperfusion

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Chronic Empaglifozin treatment reduces myocardial infarct size in non-diabetic mice through STAT-3 mediated protection on microvascular endothelial cells and reduction of oxidative stress

Antioxidants and Redox Signaling ◽

10.1089/ars.2019.7923 ◽

2020 ◽

Cited By ~ 3

Author(s):

Panagiota Efstathia Nikolaou ◽

Panagiotis Efentakis ◽

Fairouz Abu Qourah ◽

Saveria Femminò ◽

Manousos Makridakis ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Infarct Size ◽

Myocardial Infarct ◽

Microvascular Endothelial Cells ◽

Myocardial Infarct Size ◽

Diabetic Mice ◽

Microvascular Endothelial

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Human thrombopoietin reduces myocardial infarct size, apoptosis, and stunning following ischaemia/reperfusion in rats

Cardiovascular Research ◽

10.1093/cvr/cvm026 ◽

2007 ◽

Vol 77 (1) ◽

pp. 44-53 ◽

Cited By ~ 26

Author(s):

J. E. Baker ◽

J. Su ◽

A. Hsu ◽

Y. Shi ◽

M. Zhao ◽

...

Keyword(s):

Infarct Size ◽

Myocardial Infarct ◽

Myocardial Infarct Size ◽

Ischaemia Reperfusion

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Thymoquinone dose-dependently attenuates myocardial injury induced by isoproterenol in rats via integrated modulation of oxidative stress, inflammation, apoptosis, autophagy and fibrosis

10.21203/rs.3.rs-169928/v1 ◽

2021 ◽

Author(s):

Mahmoud Mohamed Farag ◽

Asmaa Ahmed Khalifa ◽

Wessam Fahmy El-Hadidy ◽

Radwa Mohamed Rashad

Keyword(s):

Oxidative Stress ◽

Myocardial Injury ◽

Cell Damage ◽

Myocardial Infarct ◽

Research Work ◽

Radical Scavenging ◽

Cardiac Biomarkers ◽

Male Rats ◽

Myocardial Infarct Size ◽

Myocardial Oxidative Stress

Abstract As rats develop myocardial infarction (MI) like lesions when injected with large doses of isoproterenol (ISO), this investigation was designed to evaluate the effects of low and high doses of thymoquinone (TQ) on ISO-induced myocardial injury in rats. Adult male rats were divided into control, TQ20 (20 mg/kg/day), TQ50 (50 mg/kg/day), and ISO, TQ20 + ISO and TQ50 + ISO groups. In these rats, biochemical, immunobiochemical and histopathological studies were carried out to evaluate myocardial oxidative stress, inflammation, apoptosis, fibrosis and autophagy and serum cardiac biomarkers. The results showed that TQ pretreatment in ISO-administered rats produced a dose-dependent significant reduction of the myocardial infarct size, markedly reduced the ISO-induced elevation in serum cardiac markers and demonstrated several other important findings related to the cardioprotective efficacy of TQ. First, this study is the first reported research work showing that TQ treatment could increase the myocardial reduced glutathione baseline level, adding an indirect antioxidant effect to its known direct free radical scavenging effect. Second, pretreatment with TQ significantly reduced the markers of myocardial oxidative stress, inflammation, fibrosis and apoptosis. Third, TQ acted as an autophagy enhancer ameliorating myocardial cell damage and dysfunction. Thus, the changes associated with ISO-induced myocardial injury were ameliorated with TQ pretreatment. Additionally, the extent of observed improvement was significantly greater with the high TQ dose than with the low dose use. These findings raise the possibility that TQ may serve as a promising prophylactic cardioprotective therapy for patients who are at risk of developing myocardial injury as in cases of MI.

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Loss of Protein Kinase Novel 1 (PKN1) is associated with mild systolic and diastolic contractile dysfunction, increased phospholamban Thr17 phosphorylation, and exacerbated ischaemia-reperfusion injury

Cardiovascular Research ◽

10.1093/cvr/cvx206 ◽

2017 ◽

Vol 114 (1) ◽

pp. 138-157 ◽

Cited By ~ 7

Author(s):

Asvi A Francois ◽

Kofo Obasanjo-Blackshire ◽

James E Clark ◽

Andrii Boguslavskyi ◽

Mark R Holt ◽

...

Keyword(s):

Protein Kinase ◽

Infarct Size ◽

Cell Injury ◽

Contractile Function ◽

Myocardial Infarct ◽

Neonatal Rat ◽

Myocardial Infarct Size ◽

Ischaemia Reperfusion ◽

Sirna Knockdown

Abstract Aims PKN1 is a stress-responsive protein kinase acting downstream of small GTP-binding proteins of the Rho/Rac family. The aim was to determine its role in endogenous cardioprotection. Methods and results Hearts from PKN1 knockout (KO) or wild type (WT) littermate control mice were perfused in Langendorff mode and subjected to global ischaemia and reperfusion (I/R). Myocardial infarct size was doubled in PKN1 KO hearts compared to WT hearts. PKN1 was basally phosphorylated on the activation loop Thr778 PDK1 target site which was unchanged during I/R. However, phosphorylation of p42/p44-MAPK was decreased in KO hearts at baseline and during I/R. In cultured neonatal rat ventricular cardiomyocytes (NRVM) and NRVM transduced with kinase dead (KD) PKN1 K644R mutant subjected to simulated ischaemia/reperfusion (sI/R), PhosTag® gel analysis showed net dephosphorylation of PKN1 during sI and early R despite Thr778 phosphorylation. siRNA knockdown of PKN1 in NRVM significantly decreased cell survival and increased cell injury by sI/R which was reversed by WT- or KD-PKN1 expression. Confocal immunofluorescence analysis of PKN1 in NRVM showed increased localization to the sarcoplasmic reticulum (SR) during sI. GC-MS/MS and immunoblot analysis of PKN1 immunoprecipitates following sI/R confirmed interaction with CamKIIδ. Co-translocation of PKN1 and CamKIIδ to the SR/membrane fraction during sI correlated with phospholamban (PLB) Thr17 phosphorylation. siRNA knockdown of PKN1 in NRVM resulted in increased basal CamKIIδ activation and increased PLB Thr17 phosphorylation only during sI. In vivo PLB Thr17 phosphorylation, Sarco-Endoplasmic Reticulum Ca2+ ATPase (SERCA2) expression and Junctophilin-2 (Jph2) expression were also basally increased in PKN1 KO hearts. Furthermore, in vivo P-V loop analysis of the beat-to-beat relationship between rate of LV pressure development or relaxation and end diastolic P (EDP) showed mild but significant systolic and diastolic dysfunction with preserved ejection fraction in PKN1 KO hearts. Conclusion Loss of PKN1 in vivo significantly reduces endogenous cardioprotection and increases myocardial infarct size following I/R injury. Cardioprotection by PKN1 is associated with reduced CamKIIδ-dependent PLB Thr17 phosphorylation at the SR and therefore may stabilize the coupling of SR Ca2+ handling and contractile function, independent of its kinase activity.

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Reciprocalcation of caveolin and HSP-72 on IPC interceded cardio-protection in the orchidectomized rats

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v12i1.4160 ◽

2021 ◽

Vol 12 (1) ◽

pp. 683-689

Author(s):

Ritesh Kumar Srivastav ◽

Tarique Mahmood Ansari ◽

Mahesh Prasad ◽

Vishal Kumar Vishwakarma ◽

Shravan Kumar Paswan ◽

...

Keyword(s):

Oxidative Stress ◽

Infarct Size ◽

Myocardial Infarct ◽

Male Rats ◽

Oxidative Stress Marker ◽

Myocardial Infarct Size ◽

Perfused Heart ◽

Oxidative Stress Parameter ◽

Cardio Protection ◽

And Oxidative Stress

Diminished testosterone levels conjoined to cardiovascular risk factor mainly myocardial infarction which broadens the risk of cardiovascular mortality referring to age. Ischemic preconditioning (IPC) is one of the interventions to shield such injury. The present study implicated the possible involvement of caveolin and heat shock protein 72 (HSP-72) during stress in orchidectomy (OCD) challenged rats. OCD was performed in male rats and kept for 6 weeks to observe the reduction in the level of testosterone. Isolated perfused heart of normal and OCD group was subjected to ischemic insult as per IPC cycle. Myocardial infarct size, haemodynamic, enzymatic and oxidative stress parameter were assessed for each heart. Diadzein (DDZ) a caveolin inhibitor was administered before the isolation of heart and it significantly decreases myocardial infarct size, release of lactate dehydrogenase, creatinine kinase and oxidative stress marker. DDZ also potentiated the effect IPC-mediated increase in the heart rate and coronary flow. The effect of caveolin inhibitor was remarkably reduced by quercetin administered before 1 h. of the administration DDZ. The findings of this study revealed that protection of myocardium induced by caveolin inhibitor pretreatment has not been lost in OCD rat heart.

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Growth-hormone-releasing peptide 6 (GHRP6) prevents oxidant cytotoxicity and reduces myocardial necrosis in a model of acute myocardial infarction

Clinical Science ◽

10.1042/cs20060103 ◽

2007 ◽

Vol 112 (4) ◽

pp. 241-250 ◽

Cited By ~ 13

Author(s):

Jorge Berlanga ◽

Danay Cibrian ◽

Luis Guevara ◽

Heberto Dominguez ◽

Jose S. Alba ◽

...

Keyword(s):

Oxidative Stress ◽

Growth Hormone ◽

Infarct Size ◽

Myocardial Injury ◽

Myocardial Infarct Size ◽

Oxidative Stress Markers ◽

Left Circumflex Artery ◽

Stress Markers ◽

Creatine Kinase Mb ◽

Igf I

Therapies aimed at enhancing cardiomyocyte survival following myocardial injury are urgently required. As GHRP6 [GH (growth hormone)-releasing peptide 6] has been shown to stimulate GH secretion and has beneficial cardiovascular effects, the aim of the present study was to determine whether GHRP6 administration reduces myocardial infarct size following acute coronary occlusion in vivo. Female Cuban Creole pigs were anaesthetized, monitored and instrumented to ensure a complete sudden left circumflex artery occlusion for 1 h, followed by a 72 h reperfusion/survival period. Animals were screened clinically before surgery and assigned randomly to receive either GHRP6 (400 μg/kg of body weight) or normal saline. Hearts were processed, and the area at risk and the infarct size were determined. CK-MB (creatine kinase MB) and CRP (C-reactive protein) levels and pathological Q-wave-affected leads were analysed and compared. Evaluation of the myocardial effect of GHRP6 also included quantitative histopathology, local IGF-I (insulin-growth factor-I) expression and oxidative stress markers. GHRP6 treatment did not have any influence on mortality during surgery associated with rhythm and conductance disturbances during ischaemia. Infarct mass and thickness were reduced by 78% and 50% respectively, by GHRP6 compared with saline (P<0.01). More than 50% of the GHRP6-treated pigs did not exhibit pathogological Q waves in any of the ECG leads. Quantitative histopathology and CK-MB and CRP serum levels confirmed the reduction in GHRP6-mediated necrosis (all P<0.05). Levels of oxidative stress markers suggested that GHRP6 prevented myocardial injury via a decrease in reactive oxygen species and by the preservation of antioxidant defence systems (all P<0.05). Myocardial IGF-I transcription was not amplified by GHRP6 treatment compared with the increase induced by the ischaemic episode in relation to expression in intact hearts (P<0.01). In conclusion, GHRP6 exhibits antioxidant effects which may partially contribute to reduce myocardial ischaemic damage.

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