Acute Myocardial Ischemia-reperfusion Research Articles

Hydrogen sulfide attenuates high fat diet-induced cardiac dysfunction via the suppression of endoplasmic reticulum stress

Diabetic cardiomyopathy is a significant contributor to the morbidity and mortality associated with diabetes and metabolic syndrome. However, the underlying molecular mechanisms that lead to its development have not been fully elucidated. Hydrogen sulfide (H2S) is an endogenously produced signaling molecule that is critical for the regulation of cardiovascular homeostasis. Recently, therapeutic strategies aimed at increasing its levels have proven cardioprotective in models of acute myocardial ischemia–reperfusion injury and heart failure. The precise role of H2S in the pathogenesis of diabetic cardiomyopathy has not yet been established. Therefore, the goal of the present study was to evaluate circulating and cardiac H2S levels in a murine model of high fat diet (HFD)-induced cardiomyopathy. Diabetic cardiomyopathy was produced by feeding mice HFD (60% fat) chow for 24 weeks. HFD feeding reduced both circulating and cardiac H2S and induced hallmark features of type-2 diabetes. We also observed marked cardiac dysfunction, evidence of cardiac enlargement, cardiac hypertrophy, and fibrosis. H2S therapy (SG-1002, an orally active H2S donor) restored sulfide levels, improved some of the metabolic perturbations stemming from HFD feeding, and attenuated HFD-induced cardiac dysfunction. Additional analysis revealed that H2S therapy restored adiponectin levels and suppressed cardiac ER stress stemming from HFD feeding. These results suggest that diminished circulating and cardiac H2S levels play a role in the pathophysiology of HFD-induced cardiomyopathy. Additionally, these results suggest that H2S therapy may be of clinical importance in the treatment of cardiovascular complications stemming from diabetes.

Variation of plasma levels of endothelin, calcitonin gene-related peptide, nitric oxide, and malondialdehyde in acute myocardial ischemia reperfusion injury in a rabbit model.

We examined the variation in plasma levels of endothelin (ET), calcitonin gene-related peptide (CGRP), nitric oxide (NO), and malondialdehyde (MDA), as well as superoxide dismutase (SOD) activity, in acute myocardial ischemia reperfusion injury in a rabbit model. Seventy rabbits were randomly assigned into 3 groups. Open-chest surgery (OCS) was performed for all rabbits. Group A (N = 20) received sham-surgery, group B (N = 25) was the reperfusion group, and group C (N = 25) was the infarction group. At 12 h after chest clo-sure, plasma ET levels in groups B and C were clearly increased, while CGRP levels were clearly decreased, particularly in group B. At 24 h after chest closure, ET levels were higher than before OCS, while there was no significant difference between groups B and C. ET in group B was decreased, while that in group C was increased at 12 h. No significant difference in CGRP was observed between 12 and 24 h after chest closure. NO levels in groups B and C at 12 h after chest closure were significantly decreased compared to those before OCS. NO levels in group B at 24, 48, and 72 h were significantly lower than those at 12 h, while those of group C were not significantly changed after 12 h. Dynamic monitoring and comparison of plasma levels of ET, CGRP, NO, and MDA as well as SOD activity revealed that appropriate intervention of these factors may reduce reperfusion injury.

Electrophysiological and antiarrhythmic properties of potassium canrenoate during myocardial ischemia-reperfusion.

Recent clinical studies have reported the potential benefit of an early mineralocorticoid receptor (MR) blockade with potassium canrenoate (PC) on ventricular arrhythmias (VAs) occurrence in patients experiencing an ST-segment elevation myocardial infarction (STEMI). However, most of the electrophysiological properties of PC demonstrated to date have been investigated in normoxic conditions, and therefore, in vitro experiments during an acute myocardial ischemia-reperfusion were lacking. We used rabbit in vitro models and standard microelectrode technique to assess the electrophysiological impact of PC during myocardial ischemia-reperfusion, including right ventricle mimicking the "border zone" existing between normal and ischemic/reperfused areas (1 µmol/L, 10 and 100 nmol/L), isolated right ventricle, and sinoatrial node (SAN) experiments (1 µmol/L, respectively). During ischemia-reperfusion, acute superfusion of PC 100 nmol/L prevented the increase in action potential (AP) duration at 90% of repolarization (APD90) dispersion between ischemic and nonischemic areas and in VAs occurrence induced by aldosterone 10 nmol/L (86 ± 3 vs 114 ± 4 milliseconds for aldosterone alone, P < .05). Potassium canrenoate also induced conduction blocks and significantly decreased Vmax during simulated ischemia (from 25 ± 5 to 12 ± 4, 14 ± 3, and 14 ± 5 V/s, respectively, for PC 1 µmol/L, 100, and 10 nmol/L, P < .05). Potassium canrenoate 1 µmol/L demonstrated cycle length (CL)-dependent effects on APD90 and on Vmax, and it also reduced SAN beating CL (from 446 ± 28 to 529 ± 24 millisecond, P < .05). Our experimental study highlights new evidence for an antiarrhythmic impact of PC during myocardial ischemia-reperfusion via multiple channels modulation. These results are in line with recent clinical trials suggesting that an early MR blockade in STEMI may be preventive of VAs.

The effects of electroacupuncture treatment on the postoperative cognitive function in aged rats with acute myocardial ischemia–reperfusion

Many literatures have proven that postoperative cognitive dysfunction (POCD) was very common in old patients after the injury of acute myocardial ischemia–reperfusion (AMIR) clinically such as the off-pump coronary artery bypass surgery (OPCAB) without definite mechanism; however, reports on the animal experiments were rarely seen. We hypothesized that AMIR could contribute to cognitive dysfunction, and this severe injury might be impeded by EA via hindering neuroinflammation and oxidative stress response as well as modulating the balance of the autonomic nervous system. The aged male Sprague Dawley rats were randomly assigned into three experimental groups: sham (sham operation), AMIR, and EA (electroacupunture treatment, acupoints GV20 and ST36+AMIR) groups. The survival rate, heart rate variability analysis, examination of pathology within the hippocampal CA1, oxidative stress, systemic inflammation and the behavior testing were evaluated by their corresponding methods. The results showed that the rats subjected to AMIR had lower survival rates, higher malondialdehyde (MDA), decreased superoxide dismutase (SOD) activity, more microglial activation, and presented evidence of severe brain injury and cognitive dysfunction on the 1st, 3rd, 7th days after reperfusion compared to sham-operated controls. Most important of all, the above damages induced by the AMIR were significantly improved by the EA treatment. Our findings indicated that EA treatment could be a neuroprotective therapy for the cognitive dysfunction induced by the AMIR event, which might be attributablefor balancing the autonomic nervous system, inhibiting the neuronic apoptosis, hindering microglial activation, attenuating oxidative stress and restraining the central and peripheral inflammation reactions.

Nlrp3 plays no role in acute cardiac infarction due to low cardiac expression

The Nlrp3 inflammasome is a protein complex consisting of NLRP3, ASC and caspase-1, that upon activation produces a potent pro-inflammatory cytokine, IL-1β. Evidence has accumulated that the Nlrp3 inflammasome contributes to delayed (>3 d) cardiac remodeling processes occurring following cardiac ischemia–reperfusion (I/R). However, from in vitro experiments it is controversial whether Nlrp3 also contributes to the more acute phase of infarct development [ 1 Zuurbier C.J. Jong W.M.C. Eerbeek O. Koeman A. Pulskens W.P. Butter L.M. et al. Deletion of the innate immune NLRP3 receptor abolishes cardiac ischemic preconditioning and is associated with decreased Il-6/STAT3 signaling. PLoS One. 2012; 7: e40643 Crossref PubMed Scopus (67) Google Scholar , 2 Sandanger O. Ranheim T. Vinge L.E. Bliksoen M. Alfsnes K. Finsen A.V. et al. The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia–reperfusion injury. Cardiovasc Res. 2013; 99: 164-174 Crossref PubMed Scopus (319) Google Scholar , 3 Jong W.M.C. Zuurbier C.J. A role for NLRP3 inflammasome in acute myocardial ischemia–reperfusion injury?. Cardiovasc Res. 2013; 99: 226 Crossref PubMed Scopus (5) Google Scholar , 4 Takahashi M. Nlrp3 inflammasome as a novel player in myocardial infarction. Int Heart J. 2014; 55: 101-105 Crossref PubMed Scopus (159) Google Scholar ]. Information on the in vivo effects of Nlrp3 deletion is currently lacking [ [4] Takahashi M. Nlrp3 inflammasome as a novel player in myocardial infarction. Int Heart J. 2014; 55: 101-105 Crossref PubMed Scopus (159) Google Scholar ]. This information is necessary in the decision whether Nlrp3 therapeutic agents should be developed for the early reperfusion phase of cardiac I/R.

GW25-e3233 Effects and mechanisms of Nicorandil anatomic no reflow after myocardial ischemia/reperfusion in rats

To establish the model of myocardial ischemia-reperfusion, to investigate effects and mechanisms of nicorandil and adenosine anatomic no reflow and ventricular remodeling after acute myocardial ischemia reperfusion in rats. To Investigate the pharmacological effects and the safety between nicorandil

HIF-1 reduces ischaemia-reperfusion injury in the heart by targeting the mitochondrial permeability transition pore.

Hypoxia-inducible factor-1 (HIF-1) has been reported to promote tolerance against acute myocardial ischaemia-reperfusion injury (IRI). However, the mechanism through which HIF-1 stabilization actually confers this cardioprotection is not clear. We investigated whether HIF-1α stabilization protects the heart against acute IRI by preventing the opening of the mitochondrial permeability transition pore (MPTP) and the potential mechanisms involved. Stabilization of myocardial HIF-1 was achieved by pharmacological inhibition of prolyl hydroxylase (PHD) domain-containing enzyme using GSK360A or using cardiac-specific ablation of von Hippel-Lindau protein (VHL(fl/fl)) in mice. Treatment of HL-1 cardiac cells with GSK360A stabilized HIF-1, increased the expression of HIF-1 target genes pyruvate dehydrogenase kinase-1 (PDK1) and hexokinase II (HKII), and reprogrammed cell metabolism to aerobic glycolysis, thereby resulting in the production of less mitochondrial oxidative stress during IRI, and less MPTP opening, effects which were shown to be dependent on HKII. These findings were further confirmed when HIF-1 stabilization in the rat and murine heart resulted in smaller myocardial infarct sizes (both in vivo and ex vivo), decreased mitochondrial oxidative stress, and inhibited MPTP opening following IRI, effects which were also found to be dependent on HKII. We have demonstrated that acute HIF-1α stabilization using either a pharmacological or genetic approach protected the heart against acute IRI by promoting aerobic glycolysis, decreasing mitochondrial oxidative stress, activating HKII, and inhibiting MPTP opening.

Differential expression of cardiac uncoupling proteins 2 and 3 in response to myocardial ischemia-reperfusion in rats

AimsWe aimed to evaluate the transcription and translation of genes for uncoupling protein 2 (UCP2) & uncoupling protein 3 (UCP3) in rat heart mitochondria of both ventricles after myocardial ischemia followed by various periods of reperfusion. Main methodsSeven groups of 8 male Wistar rats were evaluated for the effects of ischemia and also reperfusion, using Western blot of isolated mitochondrial proteins in addition to RNA extraction followed by real-time RT-PCR analysis. Key findingsIn rats with 30min of reperfusion (R30) UCP2 protein was increased 213±33%, which is meaningfully more than the control group (P<0.001). Western blot showed increase in UCP2 protein level in groups receiving reperfusion for 60min (R60), 120min (R120) and 180min (R180) as much as 152±28% (P<0.001 vs. control), 123±19% (P<0.01 vs. control) and 131±30% (P<0.01 vs. control), respectively. There was no statistically important difference in UCP2 mRNA between either right or left ventricles of ischemic and ischemia-reperfusion (IR) groups vs. control group. In the groups R180 and R240, UCP3 protein levels showed 131±27% and 102±18% increase, respectively (both P<0.001 vs. control group). However, the change in UCP3 level in other groups was not significantly different from the control group. SignificanceUCP2 and UCP3 protein levels are considerably increased in the ischemic area early after acute myocardial IR. The right ventricular UCP2 protein expression does not change, that is, effect of IR on UCP2 protein is a local process. However, UCP3 protein level increased both in ischemic area of the left ventricle and in non-ischemic area of the right ventricle.

Post-conditioning with gradually increased reperfusion provides better cardioprotection in rats.

Rapid and complete reperfusion has been widely adopted in the treatment of patients with acute myocardial infarction (AMI), but this process sometimes can cause severe reperfusion injury. This study aimed to investigate different patterns of post-conditioning in acute myocardial ischemia-reperfusion injury, and to detect the role of mitogen activated protein kinase (MAPK) during the injury. RATS WERE RANDOMLY DIVIDED INTO FIVE GROUPS: sham group, reperfusion injury (R/ I) group, gradually decreased reperfusion group (GDR group, 30/10-25/15-15/25-10/30 seconds of reperfusion/ischemia), equal reperfusion group (ER group, 20/20 seconds reperfusion/ischemia, 4 cycles), and gradually increased reperfusion group (GIR group, 10/30-15/25-25/15-30/10 seconds of reperfusion/ischemia). Acute myocardial infarction and ischemic post-conditioning models were established in the rats. Six hours after reperfusion, 3 rats from each group were sacrificed and myocardial tissues were taken to measure the expressions of phosphorylation of extracellular signal-regulated protein kinase (P-ERK), phosphorylated c-Jun N-terminal kinase (P-JNK), mitogen-activated protein kinase p38 (p38 MAPK), tumor necrosis factor-α (TNF-α), caspases-8 in the myocardial tissue, and cytochrome c in the cytosol using Western blot. Hemodynamics was measured at 24 hours after reperfusion, the blood was drawn for the determination of cardiac enzymes, and the heart tissue was collected for the measurement of apoptosis using TUNEL. One-way analysis of variance and the Q test were employed to determine differences in individual variables between the 5 groups. Three post-conditioning patterns were found to provide cardioprotection (P<0.05) compared with R/I without postconditioning. GIR provided the best cardioprotection effect, followed by ER and then GDR. Apoptotic index and serum marker levels were reduced more significantly in GIR than in ER (P<0.05). The enhanced cardioprotection provided by GIR was accompanied with significantly increased levels of P-ERK 1/2 (1.82±0.22 vs. 1.54±0.32, P<0.05), and lower levels of p-JNK, p38 MAPK, TNF-α, caspase-8, caspase-9 and cytochrome in the cytoplasm (P<0.05), compared with ER. The infarct size was smaller in the GIR group than in the ER group, but this difference was not significant (16.30%±5.22% vs. 20.57%±6.32%, P<0.05). All the measured variables were improved more significantly in the GIR group than in the GDR group (P<0.05). Gradually increased reperfusion in post-conditioning could attenuate reperfusion injury more significantly than routine method, thereby the MAPK pathway plays an important role in this process.

Rapamycin Treatment of Healthy Pigs Subjected to Acute Myocardial Ischemia-Reperfusion Injury Attenuates Cardiac Functions and Increases Myocardial Necrosis

The mammalian target of rapamycin (mTOR) pathway is a major regulator of cell immunity and metabolism. mTOR is a well-known suppressor of tissue rejection in organ transplantation. However, it has other nonimmune functions: in the cardiovascular system, it is a regulator of heart hypertrophy and locally, in coated vascular stents, it inhibits vascular wall cell growth and hence neointimal formation/restenosis. Because the mTOR pathway plays major roles in normal cell growth, metabolism, and survival, we hypothesized that inhibiting it with rapamycin before an acute myocardial ischemia-reperfusion injury (IRI) would confer cardioprotection by virtue of slowing down cardiac function and metabolism. Yorkshire pigs received either placebo or 4 mg/d rapamycin orally for 7 days before the IRI. All animals underwent median sternotomy, and the mid-left anterior descending coronary artery was occluded for 60 minutes followed by 120 minutes of reperfusion. Left ventricular pressure-volume data were collected throughout the operation. The ischemic and infarcted areas were determined by monastral blue and triphenyltetrazolium chloride staining, respectively, and plasma cardiac troponin I concentration. mTOR kinase activities were monitored in remote cardiac tissue by Western blotting with specific antibodies against mTOR substrates phosphorylating sites. Rapamycin before treatment impaired endothelial-dependent vasorelaxation, attenuated cardiac function during IRI, and increased myocardial necrosis. Western blotting confirmed effective inhibition of myocardial mTOR kinase activities. Acute myocardial IRI, in healthy pigs treated with rapamycin, is associated with decreased cardiac function and higher myocardial necrosis.

Study on the Protective Effect of Edaravone on Myocardial Ischemia Reperfusion Injury

&lt;div&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;Discussion the role of edaravone as a free radical scavenger in protective effect of thrombolysis in acute myocardial ischemia reperfusion injury. Besides compared with the control group and analyze the possible mechanism which is widely used in clinical setting. &lt;strong&gt;Method: &lt;/strong&gt;80 patients hospitalized within year 2012−2013 with acute myocardial infarction (AMI) were treated with intravenous thrombolytic therapy, and were divided into treatment group (n = 41) and control group (n = 39). Edaravone injection 30 mg + 0.9% normal saline solution 100 mL with intravenous drip, BID for 14 days was given to the treatment group before and after thrombolytic treatment. Whereas, control group was treated with intravenous drip of placebo. Both groups were monitored by echocardiography and hemodynamic monitoring, and the myocardium was measured by echocardiography. Coronary artery CT was used to determine the degree of obstruction. &lt;strong&gt;Results: &lt;/strong&gt;Compared with the control group, pain and reperfusion arrhythmia in treatment group was reduced. The area of myocardial wall movement disorder was significantly decreased (&lt;em&gt;p&lt;/em&gt; &amp;lt; 0.05), the difference was statistically significant. CT result comparing treatment group and control group and show that rate of coronary recanalization increases 1.7 times (&lt;em&gt;p &lt;/em&gt;&amp;lt; 0.01), the differences were statistically significant. &lt;strong&gt;Conclusion: &lt;/strong&gt;For acute myocardial ischemia injection of edaravone before reperfusion and combine with pharmacological treatment can alleviate myocardial ischemia reperfusion injury, effectively scavenge oxygen free radicals and improve the ability of antioxidant. Both improve the thrombolytic treatment and protective effect for acute myocardial ischemia were significant. Hence, edaravone can is a kind of new milestone in the clinical cardiovascular drugs.&lt;/p&gt;&lt;/div&gt;

Atrial ganglionated plexi stimulation may be an effective therapeutic tool for the treatment of heart failure

An autonomic imbalance, i.e., increased sympathetic tone and/or decreased parasympathetic tone is a critical characteristic of heart failure, which is associated with progressive ventricular remodeling, ventricular arrhythmia generation and disease progression. Increasing cardiac parasympathetic tone by vagus nerve stimulation has been shown to significantly improve heart failure symptoms, hemodynamics, left ventricular function and quality of life. However, cervical surgery is needed to position vagal stimulation electrode and vagus nerve stimulation may also cause some undesired side effects. Our recent studies showed that ablation of the main atrial ganglionated plexi (GP) facilitated the occurrence of ventricular arrhythmias in acute myocardial ischemic heart while low-intensity atrial GP stimulation inhibited the occurrence of ventricular arrhythmias during acute myocardial ischemia and ischemia reperfusion. Based on these results, we hypothesize that atrial GP stimulation may ameliorate autonomic dysfunction in heart failure, inhibit heart failure progression and improve heart failure prognosis.

Positive Inotropic Agents in Myocardial Ischemia–Reperfusion Injury

AbstractPositive inotropic agents should be used judiciously when managing surgical patients with acute myocardial ischemia–reperfusion injury, as use of these inotropes is not without potential adverse effects.

ASSA13-03-34 Expression of Interelenkin-17 and Intercellular Adhesion Molecule-1 on No-Reflow Phenomenon in Acute Myocardial Infarction and Reperfusion in Rat

<h3>Objective</h3> To explore the expression of Interelenkin-17 (IL-17) and Intercellular Adhesion Molecule-1 (ICAM-1) on no-reflow phenomenon in acute myocardial infarction and reperfusion in rat. <h3>Methods</h3> Tewelve healthy male Wistar rats were randomly divided into 2 groups: sham operation group (<i>n</i> = 6), and injury group (<i>n</i> = 6), the coronary artery of injury group rats were ligated for 60 min, then opened for 15 min, to establish the acute myocardial ischemia-reperfusion model of rat. The sham operation group was only put seam through the coronary artery without ligation. The electrocardiogram was checked before ligated, ligated 15 min, 30 min, 45 min and reperfused 15 min. After reperfusion for 15 min, the thioflavine S and Evens were injected from femoral venous, then the heart and blood were obtained (keeping only left ventricular). Hearts were sliced transversely into five to seven sections. Finally, observing if no-reflow phenomenon was existed after acute myocardial ischemia-reperfusion under the ultraviolet light (365nm). The level of serum IL-17 was detected by enzyme linked immunosorbent assay method and the expression of ICAM-1 was measured by immunohistochemical method. <h3>Results</h3> The experiment proved that no-reflow phenomenon was existed after acute myocardial ischemia- reperfusion. Compared with the sham group, the level of serum IL-17 of injury group was increased obviously[49.75pg/mL ± 14.06 pg/mL VS 151.67pg/mL ± 11.19pg/mL, <i>P</i> &lt; 0.01], the expression of ICAM-1 of myocardium in no-reflow area in injury group rats was increased obviously[64.74 ± 10.01 VS 316.16 ± 49.35, <i>P</i> &lt; 0.01 ], but the expression of ICAM-1 of myocardium in no ligation region in injury group rats was no statistical significance. The level of ICAM-1 was related with the level of surm IL-17. <h3>Conclusions</h3> The IL-17 and ICAM-1 play an imporant role in no-reflow injury. IL-17 can reduce the expession of ICAM-1 that can increases the inflammation and disfunction of the endothelial cell, then promote the no-reflow.

Differential membrane type 1 matrix metalloproteinase substrate processing with ischemia–reperfusion: Relationship to interstitial microRNA dynamics and myocardial function

Membrane type 1 matrix metalloproteinase (MT1-MMP) is critical to a number of proteolytic and profibrotic events. However, upstream regulation of MT1-MMP with myocardial ischemia-reperfusion remains poorly understood. MicroRNAs regulate post-transcriptional events, and in silico mapping has identified a conserved sequence in MT1-MMP for microRNA-133a. This study tested the hypothesis that changes in microRNA-133a regulation occur with myocardial ischemia-reperfusion, which contributes to time- and region-dependent changes in MT1-MMP activity and processing of MT1-MMP substrates. Yorkshire pigs (n=12) underwent ischemia-reperfusion (90 minutes ischemia and 120 minutes reperfusion), where regional preload recruitable stroke work (sonomicrometry), interstitial MT1-MMP activity (microdialysis), Smad2 abundance (immunoblotting), and interstitial microRNA-133a (polymerase chain reaction) were determined within the ischemia-reperfusion and remote regions. Human left ventricular fibroblasts were transduced with microRNA-133a and anti-microRNA-133a (lentivirus) to determine the effects on MT1-MMP protein abundance. With ischemia-reperfusion, regional preload recruitable stroke work decreased from steady state (139± 20 mm Hg to 44 ± 11 mm Hg, P<.05) within the ischemia-reperfusion region. MT1-MMP activity increased in both regions. Phosphorylated Smad2 increased within the ischemia-reperfusion region. Both invitro and invivo interstitial levels of microRNA-133a decreased with ischemia and returned to steady-state levels with reperfusion. Invitro transduction of microRNA-133a in left ventricular fibroblasts decreased MT1-MMP levels. Modulation of MT1-MMP activity and microRNA-133a exportation into the myocardial interstitium occurred in the setting of acute myocardial ischemia-reperfusion. In addition, changes in microRNA-133a expression in left ventricular fibroblasts resulted in an inverse modulation of MT1-MMP abundance. Therefore, targeting of microRNA-133a represents a potentially novel means for regulating the cascade of profibrotic events after ischemia-reperfusion.

Postconditioning with vagal stimulation attenuates local and systemic inflammatory responses to myocardial ischemia reperfusion injury in rats

To assess effects of postconditioning with the vagal stimulation (VS) on the local and systematic inflammatory responses to acute myocardial ischemia reperfusion injury (IRI). Sixty male Sprague-Dawley rats were randomly allocated into three groups: sham group, ischemia reperfusion group (IR group), and postconditioning with the VS group (POVS group). Serum levels of inflammatory cytokines during reperfusion and myocardial levels of inflammatory cytokines in both ischemic and non-ischemic regions at the end of the experiment were assayed. The infarct size was assessed by Evans blue and triphenyltetrazolium chloride staining. The infarct size was significantly reduced in the POVS group compared to the IR group. Serum levels of TNF-α at 30, 60, and 120 min of reperfusion and serum levels of HMGB-1, ICAM-1, IL-1, and IL-6 at 120 min of reperfusion were significantly lower in the POVS group than in the IR group. Myocardial levels of TNF-α, HMGB-1, ICAM-1, IL-1, and IL-6 in both ischemic and non-ischemic regions were also significantly reduced in the POVS group compared with the IR group. Postconditioning with the VS can significantly attenuate the local and systemic inflammatory responses to myocardial IRI, and provide an obvious cardioprotection.

Aquaporin-4 in the heart: expression, regulation and functional role in ischemia

Aquaporins (AQPs) are channel-forming membrane proteins highly permeable to water. AQP4 is found in mammalian hearts; however, its expression sites, regulation and function are largely unknown. The aim was to investigate cardiac AQP4 expression in humans and mice, its regulation by ischemia and hypoxia, and in particular its role in cardiac ischemic injury using AQP4 knockout (KO) mice. Comparable levels of AQP4 were detected by Western blot and qPCR in biopsies from human donor hearts and wild type C57Bl6 mouse hearts. In mice, AQP4 was expressed on cardiomyocyte plasmalemma (qPCR, Western blot, immunogold), and its mRNA decreased following ischemia/reperfusion (isolated hearts, p=0.02) and after normobaric hypoxia in vivo (oxygen fraction 10% for 1week, p<0.001). Isolated hearts from AQP4 KO mice undergoing global ischemia and reperfusion had reduced infarct size (p=0.05) and attenuated left ventricular end-diastolic pressure during reperfusion (p=0.04). Infarct size was also reduced in AQP4 KO mice 24h after left coronary artery ligation in vivo (p=0.036). AQP4 KO hearts had no compensatory change in AQP1 protein expression. AQP4 KO cardiomyocytes were partially resisted to hypoosmotic stress in the presence of hypercontracture. AQP4 is expressed in human and mouse hearts, in the latter confined to the cardiomyocyte plasmalemma. AQP4 mRNA expression is downregulated by hypoxia and ischemia. Deletion of AQP4 is protective in acute myocardial ischemia-reperfusion, and this molecule might be a future target in the treatment of acute myocardial infarction.

Expression of MicroRNA-1 and MicroRNA-21 in Different Protocols of Ischemic Conditioning in an Isolated Rat Heart Model

Background: ‘Conditioning’ [ischemic preconditioning (IPC), ischemic postconditioning (IPO) and remote ischemic preconditioning (RIPC)] the heart to render it more resistant to an episode of acute myocardial ischemia-reperfusion (I/R) injury is an endogenous cardioprotective strategy. There are several mechanisms proposed for ‘conditioning’, such as endogenous mediators or cytoprotective proteins. In recent reports, microRNAs (miRNAs) were involved in controlling the expression of myocardial ischemia-related genes. Some studies have demonstrated that cardiac miRNA-1 and miRNA-21 were significantly increased by late IPC with an increase in their target proteins [endothelial nitric oxide synthase and heat shock protein 70 (HSP70)], but their expression levels in ‘conditioning’ strategies are currently unknown. Methods: In the current study, Langendorff-perfused Sprague-Dawley rat hearts were randomly assigned to one of four groups [control group (CON group, n = 12), IPC group (n = 12), IPO group (n = 12) and RIPC group (n = 12)]. Cardiac function was digitalized and analyzed. The expression of miRNA-1 and miRNA-21 was detected by real-time reverse transcription polymerase chain reaction. The expression of HSP70, programmed cell death protein 4 (PDCD4), B-cell lymphoma/leukemia-2 (Bcl-2) and Bcl-2-associated X protein (Bax) was detected by Western blot. Cardiac infarct size and myocardial apoptosis were determined using the 2,3,5-triphenyltetrazolium chloride assay and terminal deoxynucleotidyl transferase dUTP nick end labeling assay, respectively. Results: The results revealed that miRNA-1 (233 ± 45%) and miRNA-21 (356 ± 33%) expression was up-regulated in the IPC group, but the expression of miRNA-1 was down-regulated in the RIPC (61 ± 16%) group and IPO group (61 ± 13%). The expression of PDCD4 [IPC (74 ± 11%), RIPC (81 ± 16%), IPO (83 ± 12%)], HSP70 [IPC (74 ± 5%), RIPC (81 ± 6%), IPO (67 ± 11%)] and Bax [IPC (27 ± 6%), RIPC (21 ± 3%), IPO (27 ± 4%)] was down-regulated in the conditioning groups compared with the CON group [PDCD4 (130 ± 11%), HSP70 (121 ± 11%) and Bax (63 ± 8%)]. In the conditioning hearts, infarct size [IPC (31.7 ± 4.1%), RIPC (29.6 ± 6.19%) and IPO (32.8 ± 4.71%)] and myocardial apoptosis [IPC (15.2 ± 4.21%), RIPC (17.2 ± 1.92%) and IPO (15.6 ± 4.04%)] were significantly decreased compared with the CON group (infarct size: 51.77 ± 4.3%, myocardial apoptosis: 32.8 ± 3.96%). Conclusion: We concluded that miRNA-1 and miRNA-21 expression differed in IPC, RIPC and IPO groups, and their target proteins were not inversely correlated with the miRNAs in all the conditioning groups, which revealed that the miRNAs were regulated but complicated by the different conditioning protocols.

The Intracoronary Delivery of DNAzymes Targeting Egr-1 Upon Restoration of Blood Flow Reduces Inflammation and Subsequent Tissue Damage Following Acute Myocardial Ischemia Reperfusion

The Intracoronary Delivery of DNAzymes Targeting Egr-1 Upon Restoration of Blood Flow Reduces Inflammation and Subsequent Tissue Damage Following Acute Myocardial Ischemia Reperfusion

Increased Coronary Blood Flow and Cardiac Contractile Efficiency With Intraaortic Balloon Counterpulsation in a Porcine Model of Myocardial Ischemia-Reperfusion Injury

The evaluation of the impact of intraaortic balloon pump (IABP) on postischemic coronary perfusion and myocardial contractile impairment has been so far limited to early reperfusion phase. Therefore, we analyzed the 24-hour effects of IABP on coronary blood flow (CBF) and left ventricular performance in an animal model of acute myocardial ischemia-reperfusion injury. Healthy swine (n = 20) underwent 120-minute ligation of the left anterior descending coronary artery followed by 24 hours of reperfusion. We randomly assigned the animals to have IABP placed in the descending aorta 5 minutes after reperfusion onset (n = 10) or to undergo no implantation (n = 10). We measured CBF, coronary resistance, cardiac cycle efficiency (CCE), and maximal pressure/time ratio before ischemia was induced and at 30 minutes and 1, 6, 12, and 24 hours after reperfusion began. During diastole, CBF was significantly increased in IABP compared with baseline and controls at all time points (all p < 0.001). This was also true during systole in IABP only for the first hour after reperfusion began. Additionally, both CCE and pressure/time ratio were significantly increased in IABP compared with baseline at 30 minutes and 1 hour after reperfusion began (p < 0.001). IABP was associated with enhanced CBF and cardiac efficiency in a model of acute ischemic-reperfusion injury.