scholarly journals Ivabradine Induces Cardiac Protection against Myocardial Infarction by Preventing Cyclophilin-A Secretion in Pigs under Coronary Ischemia/Reperfusion

2021 ◽  
Vol 22 (6) ◽  
pp. 2902
Author(s):  
Ignacio Hernandez ◽  
Laura Tesoro ◽  
Rafael Ramirez-Carracedo ◽  
Javier Diez-Mata ◽  
Sandra Sanchez ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Cyclophilin A ◽  
Cardiac Ischemia ◽  
Cardiac Protection ◽  
Cardiac Inflammation ◽  
Risk Areas ◽  
Lysosome Degradation ◽  
Cardiac Necrosis

In response to cardiac ischemia/reperfusion, proteolysis mediated by extracellular matrix metalloproteinase inducer (EMMPRIN) and its secreted ligand cyclophilin-A (CyPA) significantly contributes to cardiac injury and necrosis. Here, we aimed to investigate if, in addition to the effect on the funny current (I(f)), Ivabradine may also play a role against cardiac necrosis by reducing EMMPRIN/CyPA-mediated cardiac inflammation. In a porcine model of cardiac ischemia/reperfusion (IR), we found that administration of 0.3 mg/kg Ivabradine significantly improved cardiac function and reduced cardiac necrosis by day 7 after IR, detecting a significant increase in cardiac CyPA in the necrotic compared to the risk areas, which was inversely correlated with the levels of circulating CyPA detected in plasma samples from the same subjects. In testing whether Ivabradine may regulate the levels of CyPA, no changes in tissue CyPA were found in healthy pigs treated with 0.3 mg/kg Ivabradine, but interestingly, when analyzing the complex EMMPRIN/CyPA, rather high glycosylated EMMPRIN, which is required for EMMPRIN-mediated matrix metalloproteinase (MMP) activation and increased CyPA bonding to low-glycosylated forms of EMMPRIN were detected by day 7 after IR in pigs treated with Ivabradine. To study the mechanism by which Ivabradine may prevent secretion of CyPA, we first found that Ivabradine was time-dependent in inhibiting co-localization of CyPA with the granule exocytosis marker vesicle-associated membrane protein 1 (VAMP1). However, Ivabradine had no effect on mRNA expression nor in the proteasome and lysosome degradation of CyPA. In conclusion, our results point toward CyPA, its ligand EMMPRIN, and the complex CyPA/EMMPRIN as important targets of Ivabradine in cardiac protection against IR.

scholarly journals Limb remote ischemia per-conditioning protects the heart against ischemia–reperfusion injury through the opioid system in rats

2018 ◽  
Vol 96 (1) ◽  
pp. 68-75 ◽  
Author(s):  
Li Zhang ◽  
Hui Guo ◽  
Fang Yuan ◽  
Zeng-chao Hong ◽  
Yan-ming Tian ◽  
...  
Keyword(s):  
Protein Expression ◽  
Left Ventricular Function ◽  
Ventricular Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Cardiac Ischemia ◽  
Cardiac Protection ◽  
Expression Levels ◽  
Infarct Area

Remote ischemia per-conditioning (RPerC) has been demonstrated to have cardiac protection, but the underlying mechanism remains unclear. This study aimed to investigate the mechanism underlying cardiac protection of RPerC. Adult male Sprague–Dawley rats were used in this study. Cardiac ischemia/reperfusion (I/R) was induced by 30 min of occlusion and 3 h of reperfusion of the left anterior descending coronary artery. RPerC were performed by 5 min of occlusion of the right femoral artery followed by 5 min of reperfusion for three times during cardiac ischemia. The hemodynamics, left ventricular function, arrhythmia, and infarct area were measured. Protein expression levels of endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), protein kinase C-ε (PKCε), and PKCδ in the myocardium were assayed. During I/R, systolic artery pressure and left ventricular function were decreased, infarct area was increased, and arrhythmia score was increased (P < 0.05). However, changes of the above parameters were significantly attenuated in RPerC-treated rats compared with control rats (P < 0.05). The cardiac protective effects of RPerC were prevented by naloxone or glibenclamide. Also, RPerC increased the protein expression levels of eNOS, iNOS, PKCε, and PKCδ in the myocardium compared with control rats. These effects were blocked by naloxone, an opioid receptor antagonist, and glibenclamide, an ATP-sensitive K+ channel blocker (KATP). In summary, this study suggests that RPerC protects the heart against I/R injury through activation of opioid receptors and the NO–PKC–KATP channel signaling pathways.

Abstract 12788: Cardiac MicroRNA-150 Confers Cardioprotection by Directly Repressing Pro-apoptotic Small Proline-rich Protein 1a, Sprr1a in Cardiomyocytes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Tatsuya Aonuma ◽  
Bruno Moukette ◽  
Nipuni P Barupala ◽  
Il-man Kim
Keyword(s):  
Mouse Model ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Left Ventricular ◽  
Cardiac Protection ◽  
Reduced Ejection Fraction ◽  
Genome Wide ◽  
Evolutionarily Conserved ◽  
Small Proline Rich Protein ◽  
Proline Rich Protein

Background and Aims: Cardiac injury induces dynamic changes in the expression of microRNAs (miRs). For example, the evolutionarily conserved miR-150 is downregulated in patients with multiple cardiovascular diseases such as myocardial infarction (MI) and cardiomyopathies, as well as in various mouse models of heart failure (HF). MiR-150 is significantly associated with HF severity and outcome in humans. Using a systemic miR-150 knockout (KO) mouse model, we previously showed that carvedilol (Carv)/β 1 -adrenergic receptor/β-arrestin1-responsive miR-150 confers cardiac protection against MI (Left side in Figure). However, the extent to which expression of miR-150 in cardiomyocytes (CMs) regulates MI is unknown and there is a lack of mechanistic insight by which CM miR-150 modulates cardiac protection. Methods and Results: Here, we demonstrate using a novel mouse model that conditional CM-specific miR-150 KO (miR-150 cKO) in mice worsens cardiac dysfunction, stress, fibrosis and apoptosis post-MI, without affecting mortality or inflammation. Genome-wide transcriptomic analysis in miR-150 cKO mouse hearts identifies small proline-rich protein 1a (sprr1a) as a novel regulatory target of miR-150. Our mouse and CM studies further reveal that sprr1a expression is upregulated in CMs isolated from ischemic myocardium and subjected to simulated ischemia/reperfusion. In contrast, its expression is downregulated in hearts and CMs by Carv. Our human heart data also show that left ventricular sprr1a is upregulated in patients with HF with reduced ejection fraction. Mechanistically, the cardioprotective roles of CM miR-150 during MI are in part attributed to the direct and functional repression of pro-apoptotic gene sprr1a in CMs (Right side in Figure). Conclusions: These findings reveal a pivotal role for the miR-150/sprr1a axis in regulating CM function post-MI, and this novel axis could be a therapeutic target for intervention in ischemic heart disease.

scholarly journals The long noncoding RNA lncCIRBIL disrupts the nuclear translocation of Bclaf1 alleviating cardiac ischemia–reperfusion injury

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yang Zhang ◽  
Xiaofang Zhang ◽  
Benzhi Cai ◽  
Ying Li ◽  
Yuan Jiang ◽  
...  
Keyword(s):  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Pathological Process ◽  
Cardiac Ischemia

AbstractCardiac ischemia–reperfusion (I/R) injury is a pathological process resulting in cardiomyocyte death. The present study aims to evaluate the role of the long noncoding RNA Cardiac Injury-Related Bclaf1-Inhibiting LncRNA (lncCIRBIL) on cardiac I/R injury and delineate its mechanism of action. The level of lncCIRBIL is reduced in I/R hearts. Cardiomyocyte-specific transgenic overexpression of lncCIRBIL reduces infarct area following I/R injury. Knockout of lncCIRBIL in mice exacerbates cardiac I/R injury. Qualitatively, the same results are observed in vitro. LncCIRBIL directly binds to BCL2-associated transcription factor 1 (Bclaf1), to inhibit its nuclear translocation. Cardiomyocyte-specific transgenic overexpression of Bclaf1 worsens, while partial knockout of Bclaf1 mitigates cardiac I/R injury. Meanwhile, partial knockout of Bclaf1 abrogates the detrimental effects of lncCIRBIL knockout on cardiac I/R injury. Collectively, the protective effect of lncCIRBIL on I/R injury is accomplished by inhibiting the nuclear translocation of Bclaf1. LncCIRBIL and Bclaf1 are potential therapeutic targets for ischemic cardiac disease.

Abstract 19684: Nitric Oxide Protects From Cardiac Ischemia/reperfusion Damage by Blocking Activation of Extracellular Matrix Metalloproteinase Inducer EMMPRIN Through Binding to Caveolin3

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Irene Cuadrado ◽  
Ana M Martin ◽  
Marta Saura ◽  
Jose L Zamorano ◽  
Carlos Zaragoza
Keyword(s):  
Nitric Oxide ◽  
Extracellular Matrix ◽  
Matrix Metalloproteinase ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Coronary Artery Occlusion ◽  
Dependent Manner ◽  
Cardiac Protection ◽  
High Frequency Ultrasound ◽  
Extracellular Matrix Metalloproteinase Inducer

Introduction: Nitric Oxide (NO) induces cardiac protection by still unknown mechanisms. We previously found that Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) is a target of NO during ischemia/reperfusion (IR). Hypothesis: EMMPRIN is glycosylated at different locations, and high glycosylated forms of EMMPRIN are required for matrix metalloproteinase downstream activation in several cell types. In hearts subject to IR NO may inhibit EMMPRIN glycosylation. Methods: A surgical model of coronary artery occlusion. Results: We found that iNOS null mice show high glycosylated (active) forms of EMMPRIN, whereas NO producing mice also show low glycosylated EMMPRIN. Likewise, NO producing mice exhibit a significant level of cardiac protection, as shown by increased left ventricle ejection fraction detected by high frequency ultrasound, and decreased area of infarction as shown by ex vivo TTC staining. To test whether low glycosylated forms of EMMPRIN may play a role in iNOS WT cardiac protection, we found that EMMPRIN binds to caveolin-3 in healthy hearts, however, I/R prompted the disruption of low glycosylated EMMPRIN from caveolin-3 in iNOS null mice in a time dependent manner whereas a significant low glycosylated portion of EMMPRIN remained bound to caveolin-3 in iNOS WT mice. To study this effect in more detail, we found that caveolin-3 binding to low glycosylated forms of EMMPRIN, prevents downstream EMMPRIN-mediated extracellular matrix degradation through matrix metalloproteinase activation. I/R damage resulted more severe in caveolin-3 null mice, where no low glycosylated EMMPRIN was detected after reperfusion. Conclusions: We show for the first time that caveolin-3 induces nitric oxide mediated cardiac protection by preventing glycosylation of EMMPRIN in mouse hearts.

scholarly journals 406-1 Hypoxia regulatable Aav-2 vector protects against cardiac ischemia/reperfusion injury

2004 ◽  
Vol 43 (5) ◽  
pp. A533
Author(s):  
Alok S Pachori ◽  
Luis G Melo ◽  
Lunan Zhang ◽  
Richard E Pratt ◽  
Victor J Dzau
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Ischemia
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