Abstract 443: Class I Histone Deacetylases Mediate Cardiac I/R Injury and Modify the Mitochondrial Acetylome

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Daniel J Herr ◽  
Sverre E Aune ◽  
Jennifer R Bethard ◽  
Lauren E Ball ◽  
Donald R Menick
Keyword(s):  
Mass Spectrometry ◽  
Reperfusion Injury ◽  
Histone Deacetylases ◽  
Cardiac Tissue ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Class I ◽  
Mass Spectrometry Analysis ◽  
Hdac Inhibition ◽  
Class I Hdacs

Although rapid reperfusion of ischemic tissue is the treatment of choice for myocardial infarction, a significant amount of damage occurs as a result of reperfusion itself. The role of epigenetic enzymes in modulating this damage has become an area of interest in basic cardiac research. Previously, we have shown that pharmacological inhibition of the class I histone deacetylases (HDACs) with MS-275 (entinostat) preserves left-ventricular (LV) function and substantially reduces the area of infarcted tissue in isolated rat hearts subjected to ischemia-reperfusion (IR) injury. Interestingly, we have also observed that class I HDAC inhibition during 60 minutes of reperfusion alone is sufficient to protect cardiac tissue viability following I/R injury. Therefore, we hypothesized that class I HDACs mediate reperfusion injury by modulating acetylation of non-canonical pathways. To examine this, hearts from male Sprague-Dawley rats were subjected to I/R injury +/- class I HDAC inhibition during reperfusion. We then performed mass spectrometry to analyze the changes in the acetylome between sham and I/R groups with and without class I HDAC inhibition. Unexpectedly, mass spectrometry analysis revealed significant changes in the acetylation state of multiple mitochondrial enzymes. Further biochemical studies show that class I HDACs localize to the mitochondrial fraction of cardiac tissue homogenates and may modulate mitochondrial acetylation by direct or indirect mechanisms. This study emphasizes the importance of exploring class I HDAC inhibitors for protection against ischemia-reperfusion injury.

Abstract 141: Class I Histone Deacetylases Localize to Cardiac Myocyte Mitochondria and Contribute to Ischemia Reperfusion Injury

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Daniel J Herr ◽  
Mauhamad Baarine ◽  
Sverre Aune ◽  
Craig C Beeson ◽  
Lauren E Ball ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Protective Effect ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Class I ◽  
Mass Spectrometry Analysis ◽  
Hdac Inhibition ◽  
Acetylation State ◽  
Class I Hdacs

Approximately half of the damage done to the heart by a myocardial infarction occurs during reperfusion of the ischemic region while the patient is in the care of the treatment team. While many different adjuvant treatments have been explored in an attempt to attenuate this ischemia-reperfusion (I/R) injury, little progress has been made in translating novel therapies to the clinic. Recently, it was discovered that epigenetic enzymes contribute to reperfusion-induced damage, but little is known about the exact mechanism by which they exacerbate I/R injury. Previously, we have shown that class I histone deacetylase (HDACs) activity acutely exacerbates I/R injury, and that inhibition of class I HDACs with MS-275 (entinostat) preserves left-ventricular (LV) function and substantially reduces the area of infarcted tissue in isolated rat hearts subjected to ischemia-reperfusion (IR) injury. Notably, this protective effect occurs whether MS-275 is given as a pretreatment or during the reperfusion phase alone. Given the acute nature of this protective effect, we hypothesized that class I HDACs mediate reperfusion injury by modulating the acetylation state of non-histone proteins in signaling cascades that are essential to cell survival. To examine this, hearts from male Sprague-Dawley rats were subjected to ex vivo I/R injury +/- class I HDAC inhibition during reperfusion. We then performed mass spectrometry to analyze the changes in the acetylome between sham and I/R groups with and without class I HDAC inhibition. Unexpectedly, mass spectrometry analysis revealed significant changes in the acetylation state of multiple mitochondrial enzymes. Further biochemical studies show that class I HDACs localize to cardiac mitochondria and may directly modulate mitochondrial acetylation. Interestingly, these effects are correlated with a reduction in the mitochondrial respiratory capacity and mitochondrial oxidative stress during reperfusion. This study is the first to identify a class I HDAC that localizes to the mitochondria and emphasizes the importance of exploring class I HDAC inhibitors for protection against ischemia-reperfusion injury.

Abstract 405: Inhibition of Class I Histone Deacetylases at Reperfusion Attenuates Ischemia-reperfusion Injury and Modifies Mitochondrial Acetylation

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Daniel J Herr ◽  
Sverre E Aune ◽  
Donald R Menick
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Class I ◽  
Mass Spectrometry Analysis ◽  
Rate Pressure Product ◽  
Lv Function ◽  
Mitochondrial Enzymes ◽  
Reperfusion Phase

Although rapid reperfusion of ischemic tissue is the treatment of choice for myocardial infarction, much of the resultant damage occurs as a consequence of reperfusion itself. Previously, we have shown that pretreatment with MS-275, a selective class I histone deacetylase (HDAC) inhibitor, preserves left-ventricular (LV) function and substantially reduces the area of infarcted tissue in isolated rat hearts subjected to ischemia-reperfusion (IR) injury. Here, we tested the hypothesis that MS-275 treatment at reperfusion reduces LV tissue damage and improves post-ischemic LV contractile function. To do this, hearts from male Sprague-Dawley rats were isolated and perfused ex vivo on a Langendorff perfusion apparatus. A saline-filled balloon was inserted into the left ventricle of the heart to monitor ventricular pressure development throughout the experiment. Hearts were subjected to 30 minutes of ischemia, followed by 60 minutes of reperfusion. MS-275 was administered during the entire reperfusion phase, and resultant functional data were compared to untreated hearts. There was no difference in any metric of pre-ischemic contractile function between groups. 10nM MS-275 administered at reperfusion significantly improved multiple measures of LV function, including dP/dtmax, -dP/dtmax, developed pressure and rate pressure product. We also observed a significant reduction in infarct area of treated hearts compared to control, as measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Unexpectedly, mass spectrometry analysis revealed significant changes in acetylation state of multiple mitochondrial enzymes. Administration of MS-275 during the reperfusion phase of IR is sufficient to partially rescue LV function from reperfusion-induced damage. This study emphasizes the importance of exploring class I HDAC inhibitors for protection against ischemia-reperfusion.

Abstract 310: Inhibition of Class I Histone Deacetylase Activity Improves Left Ventricular Contractile Function and Cardiac Strain in Coronary Artery Occlusion-Induced Myocardial Infarction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Harinath Kasiganesan ◽  
Ludivine Renaud ◽  
Santhosh K Mani ◽  
Chou C James ◽  
Rupak Mukherjee ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Histone Deacetylases ◽  
Contractile Function ◽  
Strain Analysis ◽  
Left Ventricular ◽  
Class I ◽  
Border Zones ◽  
Cardiac Strain ◽  
Class I Hdacs

Protection from coronary heart disease-induced damage of the myocardium during myocardial infarction (MI) injury has been a target of investigation for the development of innovative cardioprotective therapies. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We observed that class I/IIb HDAC activity was nearly 5 times greater in the 7-day post-MI LV when compared to the sham ventricles. In vitro inhibition studies indicated that the majority of increased activity was due to class I HDACs. Therefore we hypothesized that suppression of class I HDACs would prevent the pathophysiological changes occurring during MI, thus improving LV pump function in post-MI myocardium. CD-1 mice were administered with the a class I HDAC inhibitor pimelic diphenylamide (PD106) or vehicle immediately after induction of MI and the treatment continued every other day for 7 days post MI. LV end-diastolic volumes, expressed as change from pre-MI values, was significantly lower in the PD106 treated mice compared to vehicle treated mice. Further, the post-MI reduction in LV ejection faction was significantly attenuated in the PD106-treated mice compared to the MI alone group. Similarly, echo cardiac strain analysis showed improved LV strain and better coherence in contractile function among infarct and border zones in PD106 MI group compared to MI only. These unique findings demonstrate that class I HDAC inhibitors may provide a novel therapeutic means to attenuate adverse post-MI LV remodeling.

Abstract 3473: Down Regulation of Class I Histone Deacetylase in the Deficit of Cardiac Lineage Protein-1 Protects Heart from Ischemia Reperfusion Injury

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Narasimman Gurusamy ◽  
Istvan Lekli ◽  
Eduardo Mascareno ◽  
M.A.Q. Siddiqui ◽  
Dipak K Das
Keyword(s):  
Cardiac Hypertrophy ◽  
Inhibitory Control ◽  
Ischemia Reperfusion ◽  
Class Ii ◽  
Left Ventricular ◽  
Class I ◽  
Down Regulation ◽  
Nuclear Expression ◽  
Cardiac Lineage ◽  
Class I Hdacs

Cardiac lineage protein-1 (CLP-1), the mouse homologue of human Hexim1 protein, exerts inhibitory control over transcriptional elongation factor-b (P-TEFb) of RNA transcript elongation, and this inhibitory control of CLP-1 over P-TEFb is released under hypertrophic stimuli. Histone deacetylases (HDACs) are known to repress the transcription of genes via maintaining compact chromatin structure. Reports have shown that class II HDACs repress the growth of myocytes, whereas, class I HDACs promotes cellular growth. A recent report suggests that inhibition of HDACs can protect the heart from ischemic injury. In the present study, we determined the role of HDACs under the down regulation of CLP-1 in ischemia reperfusion (I/R) injury and in the regulation of cardiac hypertrophy. Our results showed that the nuclear expression of class I HDACs such as HDAC1, HADC2 and HDAC3 were reduced in CLP +/− mice compared to CLP +/+ mice. In contrast to class I HDACs, class II HDACs such as HDAC4, HDAC5 and HDAC7 were not significantly altered between CLP +/− and CLP +/+ mice. When the isolated mice hearts were subjected to 30 min of ischemia followed by 120 min of reperfusion, cardiac functional parameters like aortic flow, left ventricular developed pressure and left ventricular dp/dt were significantly improved in CLP +/− mice compared to CLP +/+ mice. The percentage of myocardial infarct size after I/R injury was significantly less in CLP +/− mice than CLP +/+ mice. The occurrence of cardiac hypertrophy in CLP +/− mice was confirmed by the increased expression of fetal gene expression markers such as β-myosin heavy chain, atrial natriuretic factor and α-skeletal actin. The nuclear expression of HDAC1, HDAC2 and HDAC3 were reduced after I/R injury in CLP +/− mice compared to control CLP +/− mice. However, HDAC4, HDAC5 and HDAC7 were not altered after I/R injury in CLP +/− mice. In conclusion, our results suggest that the down regulation of class I HDACs but not class II HDACs in CLP-1 +/−mice could cause cardioprotection against I/R injury, and may also responsible for the elicitation of cardiac hypertrophy.

scholarly journals Reducing Cardiac Injury during ST-Elevation Myocardial Infarction: A Reasoned Approach to a Multitarget Therapeutic Strategy

2021 ◽  
Vol 10 (13) ◽  
pp. 2968
Author(s):  
Alessandro Bellis ◽  
Giuseppe Di Gioia ◽  
Ciro Mauro ◽  
Costantino Mancusi ◽  
Emanuele Barbato ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Reperfusion Injury ◽  
Therapeutic Strategy ◽  
Ventricular Remodeling ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
St Elevation Myocardial Infarction ◽  
Ischemic Time ◽  
St Elevation

The significant reduction in ‘ischemic time’ through capillary diffusion of primary percutaneous intervention (pPCI) has rendered myocardial-ischemia reperfusion injury (MIRI) prevention a major issue in order to improve the prognosis of ST elevation myocardial infarction (STEMI) patients. In fact, while the ischemic damage increases with the severity and the duration of blood flow reduction, reperfusion injury reaches its maximum with a moderate amount of ischemic injury. MIRI leads to the development of post-STEMI left ventricular remodeling (post-STEMI LVR), thereby increasing the risk of arrhythmias and heart failure. Single pharmacological and mechanical interventions have shown some benefits, but have not satisfactorily reduced mortality. Therefore, a multitarget therapeutic strategy is needed, but no univocal indications have come from the clinical trials performed so far. On the basis of the results of the consistent clinical studies analyzed in this review, we try to design a randomized clinical trial aimed at evaluating the effects of a reasoned multitarget therapeutic strategy on the prevention of post-STEMI LVR. In fact, we believe that the correct timing of pharmacological and mechanical intervention application, according to their specific ability to interfere with survival pathways, may significantly reduce the incidence of post-STEMI LVR and thus improve patient prognosis.

MicroRNA-330-5p inhibits NLRP3 inflammasome-mediated myocardial ischemia-reperfusion injury by targeting TIM3

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
W Zuo ◽  
R Tian ◽  
Q Chen ◽  
L Wang ◽  
Q Gu ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Abstract Background Myocardial ischemia-reperfusion injury (MIRI) is one of the leading causes of human death. Nod-like receptor protein-3 (NLRP3) inflammasome signaling pathway involved in the pathogenesis of MIRI. However, the upstream regulating mechanisms of NLRP3 at molecular level remains unknown. Purpose This study investigated the role of microRNA330-5p (miR-330-5p) in NLRP3 inflammasome-mediated MIRI and the associated mechanism. Methods Mice underwent 45 min occlusion of the left anterior descending coronary artery followed by different times of reperfusion. Myocardial miR-330-5p expression was examined by quantitative polymerase chain reaction (PCR), and miR-330-5p antagomir and agomir were used to regulate miR-330-5p expression. To evaluate the role of miR-330-5p in MIRI, Evans Blue (EB)/2, 3, 5-triphenyltetrazolium chloride (TTC) staining, echocardiography, and immunoblotting were used to assess infarct volume, cardiac function, and NLRP3 inflammasome activation, respectively. Further, in vitro myocardial ischemia-reperfusion model was established in cardiomyocytes (H9C2 cell line). A luciferase binding assay was used to examine whether miR-330-5p directly bound to T-cell immunoglobulin domain and mucin domain-containing molecule-3 (TIM3). Finally, the role of miR-330-5p/TIM3 axis in regulating apoptosis and NLRP3 inflammasome formation were evaluated using flow cytometry assay and immunofluorescence staining. Results Compared to the model group, inhibiting miR-330-5p significantly aggravated MIRI resulting in increased infarct volume (58.09±6.39% vs. 37.82±8.86%, P<0.01) and more severe cardiac dysfunction (left ventricular ejection fraction [LVEF] 12.77%±6.07% vs. 27.44%±4.47%, P<0.01; left ventricular end-diastolic volume [LVEDV] 147.18±25.82 vs. 101.31±33.20, P<0.05; left ventricular end-systolic volume [LVESV] 129.11±30.17 vs. 74.29±28.54, P<0.05). Moreover, inhibiting miR-330-5p significantly increased the levels of NLRP3 inflammasome related proteins including caspase-1 (0.80±0.083 vs. 0.60±0.062, P<0.05), interleukin (IL)-1β (0.87±0.053 vs. 0.79±0.083, P<0.05), IL-18 (0.52±0.063 vs. 0.49±0.098, P<0.05) and tissue necrosis factor (TNF)-α (1.47±0.17 vs. 1.03±0.11, P<0.05). Furthermore, TIM3 was confirmed as a potential target of miR-330-5p. As predicted, suppression of TIM3 by small interfering RNA (siRNA) ameliorated the anti-miR-330-5p-mediated apoptosis of cardiomyocytes and activation of NLRP3 inflammasome signaling pathway (Figure 1). Conclusion Overall, our study indicated that miR-330-5p/TIM3 axis involved in the regulating mechanism of NLRP3 inflammasome-mediated myocardial ischemia-reperfusion injury. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Natural Science Foundation of China Grants

scholarly journals Functional Interaction between Class II Histone Deacetylases and ICP0 of Herpes Simplex Virus Type 1

2004 ◽  
Vol 78 (13) ◽  
pp. 6744-6757 ◽  
Author(s):  
Patrick Lomonte ◽  
Joëlle Thomas ◽  
Pascale Texier ◽  
Cécile Caron ◽  
Saadi Khochbin ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Histone Deacetylases ◽  
Class Ii ◽  
Class I ◽  
Transfected Cells ◽  
Amino Terminal ◽  
Simplex Virus ◽  
Class I Hdacs

ABSTRACT This study describes the physical and functional interactions between ICP0 of herpes simplex virus type 1 and class II histone deacetylases (HDACs) 4, 5, and 7. Class II HDACs are mainly known for their participation in the control of cell differentiation through the regulation of the activity of the transcription factor MEF2 (myocyte enhancer factor 2), implicated in muscle development and neuronal survival. Immunofluorescence experiments performed on transfected cells showed that ICP0 colocalizes with and reorganizes the nuclear distribution of ectopically expressed class I and II HDACs. In addition, endogenous HDAC4 and at least one of its binding partners, the corepressor protein SMRT (for silencing mediator of retinoid and thyroid receptor), undergo changes in their nuclear distribution in ICP0-transfected cells. As a result, during infection endogenous HDAC4 colocalizes with ICP0. Coimmunoprecipitation and glutathione S-transferase pull-down assays confirmed that class II but not class I HDACs specifically interacted with ICP0 through their amino-terminal regions. This region, which is not conserved in class I HDACs but homologous to the MITR (MEF2-interacting transcription repressor) protein, is responsible for the repression, in a deacetylase-independent manner, of MEF2 by sequestering it under an inactive form in the nucleus. Consequently, we show that ICP0 is able to overcome the HDAC5 amino-terminal- and MITR-induced MEF2A repression in gene reporter assays. This is the first report of a viral protein interacting with and controlling the repressor activity of class II HDACs. We discuss the putative consequences of such an interaction for the biology of the virus both during lytic infection and reactivation from latency.

Abstract 14412: Activation of Autophagic Flux Maintains Mitochondrial Homeostasis During Cardiac Ischemia/reperfusion Injury

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Jing Yang ◽  
Geoffrey W CHO ◽  
Lihao He ◽  
Yuxin Chu ◽  
Jin He ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Systolic Function ◽  
Ischemia Reperfusion ◽  
Border Zone ◽  
Autophagic Flux ◽  
Hdac Inhibition ◽  
Infarct Border Zone ◽  
Infarct Border

Background and Hypothesis: Reperfusion injury accounts for ~50% of myocardial infarct size, and clinically efficacious therapies are lacking. Histone deacetylase (HDAC) inhibition enhances cardiomyocyte autophagic activity, mitochondria biogenesis, and blunts ischemia/reperfusion (I/R) injury when given at the time of reperfusion. However, as HDAC inhibition has pleiotropic effects, we will test whether augmentation of autophagic flux using a specific autophagy-inducing peptide, Tat-Beclin (TB), is cardioprotective. Methods: 8-12-week-old, wild-type, C57BL6 mice were randomized into three groups: vehicle control, Tat-Scrambled (TS) peptide, or Tat-Beclin (TB) peptide. Each group was subjected to I/R surgery (45min ischemia, 24h reperfusion). Infarct size, systolic function, and mitochondrial dynamics were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were used to test for cardiomyocyte specificity. Conditional cardiomyocyte ATG7 knockout (ATG7 KO) mice and ATG7 knockdown by siRNA in NRVMs were used to evaluate the role of autophagy. Results: TB treatment at reperfusion reduced infarct size by 20.1±6.3% (n=23, p<0.02) and improved systolic function. Increased autophagic flux and reduced reactive oxygen species (ROS) were observed in the infarct border zone. The cardioprotective effects of TB were abolished in ATG7 KO mice. TB increased mtDNA content in the border zone significantly. In NRVMs subjected to I/R, TB reduced cell death by 41±6% (n=12, p<0.001), decreased ROS, and increased mtDNA content significantly by ~50%. Moreover, TB promoted expression of PGC1α (a major driver of mitochondrial biogenesis) both in the infarct border zone and NRVMs subjected to I/R by ~40%, and increased levels of mitochondrial dynamics gene transcripts Drp1, Fis1, and MFN1 / 2. Conversely, ATG7 knockdown in NRVMs and cardiac ATG7 KO abolished the beneficial effects of TB on mitochondria DNA content. Conclusions: Autophagic flux is an essential process to mitigate myocardial reperfusion injury acting, at least in part, by inducing PGC1α-mediated mitochondrial biogenesis. Augmentation of autophagic flux may emerge as a viable clinical therapy to reduce reperfusion injury in myocardial infarction.

scholarly journals Baicalin Prevents Myocardial Ischemia/Reperfusion Injury Through Inhibiting ACSL4 Mediated Ferroptosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhenyu Fan ◽  
Liangliang Cai ◽  
Shengnan Wang ◽  
Jing Wang ◽  
Bohua Chen
Keyword(s):  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Receptor Protein ◽  
H9c2 Cells ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Baicalin is a natural flavonoid glycoside that confers protection against myocardial ischemia/reperfusion (I/R) injury. However, its mechanism has not been fully understood. This study focused on elucidating the role of ferroptosis in baicalin-generated protective effects on myocardial ischemia/reperfusion (I/R) injury by using the myocardial I/R rat model and oxygen–glucose deprivation/reoxygenation (OGD/R) H9c2 cells. Our results show that baicalin improved myocardial I/R challenge–induced ST segment elevation, coronary flow (CF), left ventricular systolic pressure , infarct area, and pathological changes and prevented OGD/R-triggered cell viability loss. In addition, enhanced lipid peroxidation and significant iron accumulation along with activated transferrin receptor protein 1 (TfR1) signal and nuclear receptor coactivator 4 (NCOA4)-medicated ferritinophagy were observed in in vivo and in vitro models, which were reversed by baicalin treatment. Furthermore, acyl-CoA synthetase long-chain family member 4 (ACSL4) overexpression compromised baicalin-generated protective effect in H9c2 cells. Taken together, our findings suggest that baicalin prevents against myocardial ischemia/reperfusion injury via suppressing ACSL4-controlled ferroptosis. This study provides a novel target for the prevention of myocardial ischemia/reperfusion injury.

Myocardial reperfusion injury management: erythropoietin compared with postconditioning

2009 ◽  
Vol 297 (6) ◽  
pp. H2035-H2043 ◽  
Author(s):  
Sophie Tamareille ◽  
Nehmat Ghaboura ◽  
Frederic Treguer ◽  
Dalia Khachman ◽  
Anne Croué ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Isolated Heart ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Myocardial Reperfusion ◽  
Myocardial Reperfusion Injury ◽  
Gsk 3Β ◽  
Developed Pressure

Ischemic postconditioning (IPost) and erythropoietin (EPO) have been shown to attenuate myocardial reperfusion injury using similar signaling pathways. The aim of this study was to examine whether EPO is as effective as IPost in decreasing postischemic myocardial injury in both Langendorff-isolated-heart and in vivo ischemia-reperfusion rat models. Rat hearts were subjected to 25 min ischemia, followed by 30 min or 2 h of reperfusion in the isolated-heart study. Rats underwent 45 min ischemia, followed by 24 h of reperfusion in the in vivo study. In both studies, the control group ( n = 12; ischemia-reperfusion only) was compared with IPost ( n = 16; 3 cycles of 10 s reperfusion/10 s ischemia) and EPO ( n = 12; 1,000 IU/kg) at the onset of reperfusion. The following resulted. First, in the isolated hearts, IPost or EPO significantly improved postischemic recovery of left ventricular developed pressure. EPO induced better left ventricular developed pressure than IPost at 30 min of reperfusion (73.18 ± 10.23 vs. 48.11 ± 7.92 mmHg, P < 0.05). After 2 h of reperfusion, the infarct size was significantly lower in EPO-treated hearts compared with IPost and control hearts (14.36 ± 0.60%, 19.11 ± 0.84%, and 36.21 ± 4.20% of the left ventricle, respectively; P < 0.05). GSK-3β phosphorylation, at 30 min of reperfusion, was significantly higher with EPO compared with IPost hearts. Phosphatidylinositol 3-kinase and ERK1/2 inhibitors abolished both EPO- and IPost-mediated cardioprotection. Second, in vivo, IPost and EPO induced an infarct size reduction compared with control (40.5 ± 3.6% and 28.9 ± 3.1%, respectively, vs. 53.7 ± 4.3% of the area at risk; P < 0.05). Again, EPO decreased significantly more infarct size and transmurality than IPost ( P < 0.05). In conclusion, with the use of our protocols, EPO showed better protective effects than IPost against reperfusion injury through higher phosphorylation of GSK-3β.

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