The myocardial infarct size-limiting and antiarrhythmic effects of acyl-CoA:Cholesterol acyltransferase inhibitor VULM 1457 protect the hearts of diabetic–hypercholesterolaemic rats against ischaemia/reperfusion injury both in vitro and in vivo

2007 ◽  
Vol 576 (1-3) ◽  
pp. 114-121 ◽  
Author(s):  
Adriana Adameová ◽  
Táňa Ravingerová ◽  
Pavel Švec ◽  
Viera Faberová ◽  
Magdaléna Kuželová
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Myocardial Infarct ◽  
Myocardial Infarct Size ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Antiarrhythmic Effects

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

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.

scholarly journals Overexpression of SERCA2a Alleviates Cardiac Microvascular Ischemic Injury by Suppressing Mfn2-Mediated ER/Mitochondrial Calcium Tethering

2021 ◽  
Vol 9 ◽  
Author(s):  
Feng Tian ◽  
Ying Zhang
Keyword(s):  
Endoplasmic Reticulum ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Ischemic Injury ◽  
Calcium Overload ◽  
Mitochondrial Calcium ◽  
Myocardial Infarct Size ◽  
Hypoxic Injury

Our previous research has shown that type-2a Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) undergoes posttranscriptional oxidative modifications in cardiac microvascular endothelial cells (CMECs) in the context of excessive cardiac oxidative injury. However, whether SERCA2a inactivity induces cytosolic Ca2+ imbalance in mitochondrial homeostasis is far from clear. Mitofusin2 (Mfn2) is well known as an important protein involved in endoplasmic reticulum (ER)/mitochondrial Ca2+ tethering and the regulation of mitochondrial quality. Therefore, the aim of our study was to elucidate the specific mechanism of SERCA2a-mediated Ca2+ overload in the mitochondria via Mfn2 tethering and the survival rate of the heart under conditions of cardiac microvascular ischemic injury. In vitro, CMECs extracted from mice were subjected to 6 h of hypoxic injury to mimic ischemic heart injury. C57-WT and Mfn2KO mice were subjected to a 1 h ischemia procedure via ligation of the left anterior descending branch to establish an in vivo cardiac ischemic injury model. TTC staining, immunohistochemistry and echocardiography were used to assess the myocardial infarct size, microvascular damage, and heart function. In vitro, ischemic injury induced irreversible oxidative modification of SERCA2a, including sulfonylation at cysteine 674 and nitration at tyrosine 294/295, and inactivation of SERCA2a, which initiated calcium overload. In addition, ischemic injury-triggered [Ca2+]c overload and subsequent [Ca2+]m overload led to mPTP opening and ΔΨm dissipation compared with the control. Furthermore, ablation of Mfn2 alleviated SERCA2a-induced mitochondrial calcium overload and subsequent mito-apoptosis in the context of CMEC hypoxic injury. In vivo, compared with that in wild-type mice, the myocardial infarct size in Mfn2KO mice was significantly decreased. In addition, the findings revealed that Mfn2KO mice had better heart contractile function, decreased myocardial infarction indicators, and improved mitochondrial morphology. Taken together, the results of our study suggested that SERCA2a-dependent [Ca2+]c overload led to mitochondrial dysfunction and activation of Mfn2-mediated [Ca2+]m overload. Overexpression of SERCA2a or ablation of Mfn2 expression mitigated mitochondrial morphological and functional damage by modifying the SERCA2a/Ca2+-Mfn2 pathway. Overall, these pathways are promising therapeutic targets for acute cardiac microvascular ischemic injury.

scholarly journals 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

2017 ◽  
Vol 114 (1) ◽  
pp. 138-157 ◽  
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.

The effect of relaxin on myocardial ischaemia-reperfusion injury and histamine release in vitro and in vivo

1996 ◽  
Vol 45 (S1) ◽  
pp. S27-S28 ◽  
Author(s):  
E. Masini ◽  
D. Salvemini ◽  
L. Mugnai ◽  
M. G. Bello ◽  
D. Bani ◽  
...  
Keyword(s):  
Histamine Release ◽  
Reperfusion Injury ◽  
Myocardial Ischaemia ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Release In Vitro

scholarly journals IL-4 Alleviates Ischaemia-Reperfusion Injury by Inducing Kupffer Cells M2 Polarization via STAT6-JMJD3 Pathway after Rat Liver Transplantation

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Minghua Deng ◽  
Jingyuan Wang ◽  
Hao Wu ◽  
Menghao Wang ◽  
Ding Cao ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Reperfusion Injury ◽  
Kupffer Cells ◽  
Interleukin 4 ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
M2 Polarization ◽  
Hepatocellular Apoptosis

Background. Liver ischaemia-reperfusion injury (IRI) remains a problem in liver transplantation. Interleukin-4 (IL-4) has been found to reduce liver IRI, but the exact mechanism remains unclear. Methods. Donor livers were infused with recombinant IL-4 or normal saline during cold storage, and the hepatocellular apoptosis and the inflammatory response were detected. The effect of IL-4 treatment on Kupffer cells (KCs) polarization and expression of the STAT6-JMJD3 pathway was evaluated in vivo and in vitro. KCs in donor livers were depleted by clodronate liposome treatment or JMJD3 was inhibited by GSK-J4 before liver transplantation to determine whether the protective effect of IL-4 treatment was dependent on KCs. Results. IL-4 treatment decreased sALT and sAST levels and alleviated hepatocellular apoptosis and inflammation at 6 h after liver transplantation. IL-4 treatment induced KCs alternatively activated (M2) polarization in vitro and in vivo, and the expression of STAT6 and JMJD3 was increased. JMJD3 knockdown abolished KCs M2 polarization and reduced the antiapoptotic and anti-inflammatory effects induced by IL-4 treatment in vitro. In addition, the protection of IL-4 treatment against IRI induced by liver transplantation was significantly reduced after the depletion of KCs or the inhibition of JMJD3 in donor livers. Conclusions. IL-4 treatment-induced KCs M2 polarization was dependent on the STAT6-JMJD3 pathway and protected liver grafts from IRI after liver transplantation.

scholarly journals Luteolin Modulates SERCA2a Leading to Attenuation of Myocardial Ischemia/ Reperfusion Injury via Sumoylation at Lysine 585 in Mice

2018 ◽  
Vol 45 (3) ◽  
pp. 883-898 ◽  
Author(s):  
Yinping Du ◽  
Ping Liu ◽  
Tongda Xu ◽  
Defeng Pan ◽  
Hong Zhu ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Heart Function ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Myocardial Ischemia Reperfusion

Background/Aims: The myocardial sarcoplasmic reticulum calcium ATPase (SERCA2a) is a pivotal pump responsible for calcium cycling in cardiomyocytes. The present study investigated the effect of luteolin (Lut) on restoring SERCA2a protein level and stability reduced by myocardial ischemia/reperfusion (I/R) injury. We verified a hypothesis that Lut protected against myocardial I/R injury by regulating SERCA2a SUMOylation. Methods: The hemodynamic data, myocardial infarct size of intact hearts, apoptotic analysis, mitochondrial membrane potential (ΔΨm), the level of SERCA2a SUMOylation, and the activity and expression of SERCA2a were examined in vivo and in vitro to clarify the cardioprotective effects of Lut after SUMO1 was knocked down or over-expressed. The putative SUMO conjugation sites in mouse SERCA2a were investigated as the possible regulatory mechanism of Lut. Results: Initially, we found that Lut reversed the SUMOylation and stability of SERCA2a as well as the expression of SUMO1, which were reduced by I/R injury in vitro. Furthermore, Lut increased the expression and activity of SERCA2a partly through SUMO1, thus improving ΔΨm and reducing apoptotic cells in vitro and promoting the recovery of heart function and reducing infarct size in vivo. We also demonstrated that SUMO acceptor sites in mouse SERCA2a involving lysine 585, 480 and 571. Among the three acceptor sites, Lut enhanced SERCA2a stability via lysine 585. Conclusions: Our results suggest that Lut regulates SERCA2a through SUMOylation at lysine 585 to attenuate myocardial I/R injury.

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