Targeting mitochondrial shape: at the heart of cardioprotection.

There remains an unmet need to identify novel therapeutic strategies capable of protecting the myocardium against the detrimental effects of acute ischemia-reperfusion injury (IRI), to reduce myocardial infarct (MI) size and prevent the onset of heart failure (HF) following acute myocardial infarction (AMI). In this regard, perturbations in mitochondrial morphology with an imbalance in mitochondrial fusion and fission can disrupt mitochondrial metabolism, calcium homeostasis, and reactive oxygen species production, factors which are all known to be critical determinants of cardiomyocyte death following acute myocardial IRI. As such, therapeutic approaches directed at preserving the morphology and functionality of mitochondria may provide an important strategy for cardioprotection. In this article, we provide an overview of the alterations in mitochondrial morphology which occur in response to acute myocardial IRI, and highlight the emerging therapeutic strategies for targeting mitochondrial shape to preserve mitochondrial function which have the future therapeutic potential to improve health outcomes in patients presenting with AMI.

Cardiac phospholipidome is altered during ischemia and reperfusion in an ex vivo rat model.

Acute myocardial infarction (AMI) is the leading cause of death, morbidity, and health costs worldwide. In AMI, a sudden blockage of blood flow causes myocardial ischemia and cell death. Reperfusion after ischemia has paradoxical effects and may exacerbate the myocardial injury, a process known as ischemic reperfusion injury. In this work we evaluated the lipidome of isolated rat hearts, maintained in controlled perfusion (CT), undergoing global ischemia (ISC) or ischemia followed by reperfusion (IR). 153 polar lipid levels were significantly different between conditions. 48 features had q < 0.001 and included 8 phosphatidylcholines and 4 lysophospholipids, which were lower in ISC compared to CT, and even lower in the IR group, suggesting that IR induces more profound changes than ISC. We observed that the levels of 16 alkyl acyl phospholipids were significantly altered during ISC and IR. Overall, these data indicate that myocardial lipid remodelling and possibly damage occurs to a greater extent during reperfusion. The adaptation of cardiac lipidome during ISC and IR described is consistent with the presence of oxidative damage and may reflect the impact of AMI on the lipidome at the cellular level and provide new insights into the role of lipids in the pathophysiology of acute myocardial ischemia/reperfusion injury.

[Effect of electroacupuncture preconditioning on the expressions of NF-κB p65, IκBα and IKKß in myocardial tissue of the rats with acute myocardial ischemia-reperfusion injury].

OBJECTIVE: To observe the effect of electroacupuncture (EA) preconditioning on the expressions of nuclear transcription factors-kappa B (NF-κB) p65, NF-κB inhibitor (IκB) α and IκB kinase (IKK) ß in rats with acute myocardial ischemia-reperfusion injury (MIRI) and to explore the mechanism of EA on heart meridian in relieving MIRI. METHODS: A total of 40 SD rats were randomized into a sham-operation group, a model group, an EA heart meridian group and an EA lung meridian group, 10 rats in each one. In the EA heart meridian group, acupuncture was applied to "Shenmen" (HT 7) and "Tongli" (HT 5). In the EA lung meridian group, acupuncture was applied to "Taiyuan" (LU 9) and "Lieque" (LU 7). In these two groups, EA was exerted for 20 min each time, 1 V in voltage and 2 Hz in frequency once a day. A total of 7-day EA stimulation was required before model duplication. In the model group, the EA heart meridian group and the EA lung meridian group, using ligating left anterior descending coronary artery to establish the acute MIRI models. In the sham-operation group, the chest was open, but no ligation was exerted, just the needle was penetrated through the corresponding sites for one time. The electrocardiogram (ECG) was detected and ST segment displacement was analyzed. Using Western blot method, the relative expressions of NF-κB p65, IκBα and IKKß in myocardial tissue were determined in each group. Using ELISA method, the levels of serum IL-1ß and IL-10 were determined in each group. RESULTS: Compared with the sham-operation group, ST segment displacement value was elevated 30 min after ligating and reperfusion for 120 min in the model group (P<0.05), and the value in the EA heart meridian group was lower than the model group and the EA lung meridian group (P<0.05). Compared with the sham-operation group, the expressions of NF-κB p65 and IKKß in myocardial tissue were increased (P<0.05) and the expression of IκBα reduced in the rats of the model group (P<0.05). Compared with the model group, the expressions of NF-κB p65 and IKKß in myocardial tissue were reduced (P<0.05) and the expressions of IκBα increased in the rats of the EA heart meridian group and the EA lung meridian group (P<0.05). Compared with the EA lung meridian group, the expressions of NF-κB p65 and IKKß in myocardial tissue were reduced (P<0.05) and the expression of IκBα increased in the rats of the EA heart meridian group (P<0.05). Compared with the sham-operation group, the serum level of IL-1ß was increased (P<0.05) and IL-10 reduced in the model group (P<0.05). Compared with the model group, the serum level of IL-1ß was reduced (P<0.05) and IL-10 increased in the EA heart meridian group and the level of IL-1ß was was reduced in the EA lung meridian group (P<0.05). Compared with the EA lung meridian group, the serum level of IL-1ß was reduced (P<0.05) and IL-10 increased in the EA heart meridian group (P<0.05). CONCLUSION: Electroacupuncture preconditioning at heart meridian acupoints obviously alleviates acute MIRI. IKK/IκB/NF-κB signaling pathway possibly participates in the protective mechanism of electroacupuncture preconditioning on acute MIRI.

[Effects of electroacupuncture preconditioning on expression of aquaporin-1 and activity of protein kinase C in myocardium of rats with acute myocardial ischemia-reperfusion injury].

OBJECTIVE: To explore the partial action mechanism and the myocardial protective effect differences between electroacupuncture (EA) preconditioning at "Neiguan"(PC 6) and "Taiyuan"(LU 9) in rats with acute myocardial ischemia-reperfusion injury. METHODS: Ninety-six Wistar rats were randomly assigned into a sham-operation group, a model group, a Neiguan group and a Taiyuan group, 24 rats in each one. The rats in the Neiguan group and Taiyuan group were treated with EA (2 Hz in frequency, 1 mA in intensity) at "Neiguan" (PC 6) and "Taiyuan" (LU 9) respectively, 20 min per treatment, once a day for consecutive 7 days. The rats in the sham-operation group and model group were treated with immobilization for the same time, and no EA was given. The model of myocardial ischemia-reperfusion injury was established in the model group, Neiguan group and Taiyuan group 24 h after the end of EA, while the rats in the sham-operation group were treated with sham operation (no ligation was made during surgery). The myocardial ischemic size, infarction size, activity of protein kinase C (PKC) and expression of aquaporin1 (AQP1) in each group were detected. RESULTS: Compared with sham-operation group, the myocardial ischemic size, infarction size, AQP1 expression and PKC activity in the model group were significantly increased (all P<0.01); compared with the model group and Taiyuan group, the myocardial ischemic size, infarction size, PKC activity and AQP1 expression were significantly decreased in the Neiguan group (P<0.01, P<0.05). By Pearson correlation analysis, the changes of AQP1 expression were positively correlated with those of PKC activity after EA preconditioning. CONCLUSIONS: EA preconditioning at "Neiguan" (PC 6) could significantly decrease myocardial AQP1 expression and PKC activity in rats with acute myocardial ischemia-reperfusion injuing, but the effect of EA preconditioning at "Taiyuan"(LU 9) is not obvious; its protective effect is likely to be achieved by inhibiting PKC activity and AQP1 expression.

Fenofibrate protects against acute myocardial I/R injury in rat by suppressing mitochondrial apoptosis as decreasing cleaved caspase-9 activation.

BACKGROUND AND AIMS: Peroxisome proliferator-activated receptor-α (PPAR-α) activation has been reported to reduce myocardial ischemia-reperfusion (I/R) injury by inhibiting cell apoptosis. However, the antiapoptotic mechanism of PPAR-α is still unknown. Fenofibrate is a PPAR-α agonist In the present study, we investigate the effects and relevant mechanism of fenofibrate on experimental myocardial ischemia-reperfusion (I/R) injury in rats. METHODS: Adult male Wistar rats were pretreated with fenofibrate (80 mg/kg) daily for a period of 7 days. After the treatment period, myocardial I/R injury model was made by left anterior descending coronary artery ligation for 45 min and reperfusion for 120 min. Myocardial infarct size, malondialdehyde (MDA) cleaved-caspase-9 protein expression, PPARα and uncoupling protein 2 (UCP2) mRNA levels in myocardial tissue were detected Cell apoptosis was detected by Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Serum lactate dehydrogenase and creatine kinase activities were measured in rats pretreated with fenofibrate The ultrastructure of myocardial tissues was observed. RESULTS: Significant increases in myocardial cell apoptosis, malondialdehyde (MDA) level and cleaved-caspase-9 protein expression level in myocardial tissue were observed, along with reductions of PPARα and uncoupling protein 2 (UCP2) mRNA levels in myocardial tissue of the experimental myocardial ischemia-reperfusion (I/R) injury in rats. Impaired mitochondria were also observed under electron microscopic. However, pretreatment of ischemia/reperfusion rats with fenofibrate brought the biochemical parameters and related genes expression levels to near normalcy, indicating the protective effect of fenofibrate against myocardial ischemia/reperfusion injury in rats. CONCLUSIONS: The PPAR-α activator fenofibrate conferred cytoprotective effect against myocardial ischemia-reperfusion (I/R) injury in rats. Associated mechanisms involved decreased cleaved-caspase-9 expression and decreased cell apoptosis.

Effects of electroacupuncture preconditioning on expression of aquaporin-1 and activity of protein kinase C in myocardium of rats with acute myocardial ischemia-reperfusion injury / 中国针灸

<p><b>OBJECTIVE</b>To explore the partial action mechanism and the myocardial protective effect differences between electroacupuncture (EA) preconditioning at "Neiguan"(PC 6) and "Taiyuan"(LU 9) in rats with acute myocardial ischemia-reperfusion injury.</p><p><b>METHODS</b>Ninety-six Wistar rats were randomly assigned into a sham-operation group, a model group, a Neiguan group and a Taiyuan group, 24 rats in each one. The rats in the Neiguan group and Taiyuan group were treated with EA (2 Hz in frequency, 1 mA in intensity) at "Neiguan" (PC 6) and "Taiyuan" (LU 9) respectively, 20 min per treatment, once a day for consecutive 7 days. The rats in the sham-operation group and model group were treated with immobilization for the same time, and no EA was given. The model of myocardial ischemia-reperfusion injury was established in the model group, Neiguan group and Taiyuan group 24 h after the end of EA, while the rats in the sham-operation group were treated with sham operation (no ligation was made during surgery). The myocardial ischemic size, infarction size, activity of protein kinase C (PKC) and expression of aquaporin1 (AQP1) in each group were detected.</p><p><b>RESULTS</b>Compared with sham-operation group, the myocardial ischemic size, infarction size, AQP1 expression and PKC activity in the model group were significantly increased (all<0.01); compared with the model group and Taiyuan group, the myocardial ischemic size, infarction size, PKC activity and AQP1 expression were significantly decreased in the Neiguan group (<0.01,<0.05). By Pearson correlation analysis, the changes of AQP1 expression were positively correlated with those of PKC activity after EA preconditioning.</p><p><b>CONCLUSIONS</b>EA preconditioning at "Neiguan" (PC 6) could significantly decrease myocardial AQP1 expression and PKC activity in rats with acute myocardial ischemia-reperfusion injuing, but the effect of EA preconditioning at "Taiyuan"(LU 9) is not obvious; its protective effect is likely to be achieved by inhibiting PKC activity and AQP1 expression.</p>

Effect of umbilical cord mesenchymal stem cells on VEGF and MCP-1 of acute myocardial ischemia-reperfusion injury in rats / 国际生物医学工程杂志

Objective To investigate the effects of human umbilical cord mesenchymal stem cells (UC-MSCs ) on vascular endothelial growth factor ( VEGF ) and monocyte chemoattractant protein-1 ( MCP-1 ) of acute myocardial ischemia-reperfusion (AMI-R) injury in rats. Methods 24 Sprague-Dawley rats were randomly divided into sham group, AMI-R group and UCMSCs treatment groups on average. The rats were sacrificed on the 10th day after UCMSCs transplantation, and the myocardial tissues below the ligature were taken. The mRNA and protein expressions of MCP-1 of the tissue were detected by RT-PCR and Western Blot respectively, and the expression of VEGF protein was detected by immunohistochemistry. Results The relative expression levels of MCP-1 mRNA and the protein in UCMSCs group were significantly lower than those in sham group and AMI-R group (all P<0.05). The expression of VEGF protein in UCMSCs group was significantly higher than that in sham group and AMI-R group, the differences were statistically significant(all P<0.05). Conclusion UCMSCs transplantation can promote the angiogenesis and decrease the inflammation reaction in the treatment of acute myocardial ischemia-reperfusion injury.

Effects of Ang â ¡ perfusion on transmural heterogeneous of Cx43 in acute myocardial ischemia reperfusion.

OBJECTIVE: To observe the effects of angiotensin Ⅱ(Ang Ⅱ) perfusion on transmural heterogeneity of Cx43 expression in the rabbit model with acute myocardial ischemia reperfusion (MIR), and investigate the role of rennin-angiotensin system in malignant ventricular arrhythmia induced by MIR. METHODS: Twenty rabbits were randomly divided into MIR group (n = 10) and Ang Ⅱ group (n = 10). MIR model was produced with traditional ligation and opening of the anterior descending coronary artery in all animal. The hearts in vitro in the MIR group and the Ang Ⅱ group were perfused with simply improved Tyrode's solution and containing Ang Ⅱ Tyrode's solution respectively. 90% monophasic action potential repolarization duration, transmural dispersion of repolarization, Cx43 protein (Cx43-pro) and mRNA (Cx43-Cq) expression in subepicardial, midmyocardial and subendocardial myocardium were measured in both groups. The greatest differences of Cx43-pro and Cx43-Cq among three myocardial layers were calculated and shown with ΔCx43-pro and ΔCx43-Cq respectively. RESULTS: After Ang Ⅱ perfusion, 90% monophasic action potential repolarization duration among three myocardial layer were significantly prolonged (P < 0.05 and P < 0.01), and transmural dispersion of repolarization also significantly increased compared with the MIR group (P < 0.05). Compare with the MIR group, three myocardial Cx43-pro and Cx43-Cq expression in the Ang Ⅱ group were significantly decreased (P < 0.05 and P < 0.01), but ΔCx43-pro and ΔCx43-Cq were significant increased. CONCLUSIONS: Renin-angiotensin system increases transmural heterogeneity of Cx43 expression in the rabbit model with MIR by Ang Ⅱ, and enlarge transmural dispersion of repolarization among three myocardial layers of left ventricular which induces malignant ventricular arrhythmia.

Experimental study on the effects of Yangxinshi tablets in the prevention and treatment of chronic ischemic heart failure and acute myocardial ischemia reper-fusion injury / 药学实践杂志

Objective Experimental study on effects of Yangxinshi tablets in the prevention and treatment of chronic is-chemic heart failure and acute myocardial ischemia reperfusion injury in order to provide a theoretical basis for its clinical appli-cation .Method Rat model of chronic ischemic heart failure and acute ischemia reperfusion mouse model of myocardial infarc-tion were constructed through coronary artery ligation .Those animals were randomized to sham operation group ,model group , positive drug group ,high Yangxinshi tablet dose group ,middle Yangxinshi tablet dose group ,low Yangxinshi tablet dose group .Rat electrocardiogram ,ultrasound ,ACE ,ACD ,TNF-a ,mouse myocardial infarction area ,CK ,LDH ,SOD and relat-ed factors were recorded during pre-dosing and post-dosing after modeling .Morphological changes were observed with cardiac pathological section .Results The biochemical indicators in model group were significantly different from sham operation group with statistical significance (P<0 .001) .Compared to the model group ,positive drug group and high Yangxinshi tablet dose group exhibited biochemical differences with statistical significance (P<0 .001 ,P<0 .01 ,P<0 .05) ,significant myocardial in-farction area reduction (P<0 .01 ,P<0 .05) ,improvement in myocardial cells and reduction in the cell infiltration .Conclusion Yangxinshi tablets have preventive and therapeutic effects on chronic ischemic heart failure and acute ischemia reperfusion in-jury .

Effects of Ang II perfusion on transmural heterogeneous of Cx43 in acute myocardial ischemia reperfusion

Objective: To observe the effects of angiotensin II(Ang II) perfusion on transmural heterogeneity of Cx43 expression in the rabbit model with acute myocardial ischemia reperfusion (MIR), and investigate the role of rennin-angiotensin system in malignant ventricular arrhythmia induced by MIR. Methods: Twenty rabbits were randomly divided into MIR group (n = 10) and Ang II group (n = 10). MIR model was produced with traditional ligation and opening of the anterior descending coronary artery in all animal. The hearts in vitro in the MIR group and the Ang II group were perfused with simply improved Tyrode's solution and containing Ang II Tyrode's solution respectively. 90% monophasic action potential repolarization duration, transmural dispersion of repolarization, Cx43 protein (Cx43-pro) and mRNA (Cx43-Cq) expression in subepicardial, midmyocardial and subendocardial myocardium were measured in both groups. The greatest differences of Cx43-pro and Cx43-Cq among three myocardial layers were calculated and shown with ΔCx43-pro and ΔCx43-Cq respectively. Results: After Ang II perfusion, 90% monophasic action potential repolarization duration among three myocardial layer were significantly prolonged (P < 0.05 and P < 0.01), and transmural dispersion of repolarization also significantly increased compared with the MIR group (P < 0.05). Compare with the MIR group, three myocardial Cx43-pro and Cx43-Cq expression in the Ang II group were significantly decreased (P < 0.05 and P < 0.01), but ΔCx43-pro and ΔCx43-Cq were significant increased. Conclusions: Renin-angiotensin system increases transmural heterogeneity of Cx43 expression in the rabbit model with MIR by Ang II, and enlarge transmural dispersion of repolarization among three myocardial layers of left ventricular which induces malignant ventricular arrhythmia.

Effects of Ang Ⅱ perfusion on transmural heterogeneous of Cx43 in acute myocardial ischemia reperfusion

OBJECTIVE@#To observe the effects of angiotensin Ⅱ(Ang Ⅱ) perfusion on transmural heterogeneity of Cx43 expression in the rabbit model with acute myocardial ischemia reperfusion (MIR), and investigate the role of rennin-angiotensin system in malignant ventricular arrhythmia induced by MIR.@*METHODS@#Twenty rabbits were randomly divided into MIR group (n = 10) and Ang Ⅱ group (n = 10). MIR model was produced with traditional ligation and opening of the anterior descending coronary artery in all animal. The hearts in vitro in the MIR group and the Ang Ⅱ group were perfused with simply improved Tyrode's solution and containing Ang Ⅱ Tyrode's solution respectively. 90% monophasic action potential repolarization duration, transmural dispersion of repolarization, Cx43 protein (Cx43-pro) and mRNA (Cx43-Cq) expression in subepicardial, midmyocardial and subendocardial myocardium were measured in both groups. The greatest differences of Cx43-pro and Cx43-Cq among three myocardial layers were calculated and shown with ΔCx43-pro and ΔCx43-Cq respectively.@*RESULTS@#After Ang Ⅱ perfusion, 90% monophasic action potential repolarization duration among three myocardial layer were significantly prolonged (P < 0.05 and P < 0.01), and transmural dispersion of repolarization also significantly increased compared with the MIR group (P < 0.05). Compare with the MIR group, three myocardial Cx43-pro and Cx43-Cq expression in the Ang Ⅱ group were significantly decreased (P < 0.05 and P < 0.01), but ΔCx43-pro and ΔCx43-Cq were significant increased.@*CONCLUSIONS@#Renin-angiotensin system increases transmural heterogeneity of Cx43 expression in the rabbit model with MIR by Ang Ⅱ, and enlarge transmural dispersion of repolarization among three myocardial layers of left ventricular which induces malignant ventricular arrhythmia.

Pinocembrin reduces cardiac arrhythmia and infarct size in rats subjected to acute myocardial ischemia/reperfusion.

Oxidative stress plays an important role in the pathogenesis of ischemia/reperfusion (I/R) injury induced by cardiac dysfunction. Pinocembrin (5,7-dihydroxyflavanone) is a flavonoid found in propolis and in rhizomes of fingerroot (Boesenbergia pandurata) that is reported to have pharmacological properties including antimicrobial, antioxidant, and anti-inflammatory activities. The cardioprotective effects of pinocembrin in an I/R model were investigated in this study. Male Wistar rats (n = 20) were randomly divided into 2 groups to receive either pinocembrin (30 mg/kg body weight) or the vehicle intravenously. Thirty minutes later, the left anterior descending coronary artery of each rat was ligated for 30 min, and then reperfusion was allowed for 120 min. Cardiac function improved in the pinocembrin-treated group: the time to first ventricular fibrillation (VF) was significantly longer in the treated group (550 ± 54 s) than in the vehicle-only control group (330 ± 27 s) (p < 0.05). VF incidence and arrhythmia score were lower and infarcts were 49% smaller in the pinocembrin-treated group than in the control group (p < 0.05). In the pinocembrin-treated group, malondialdehyde levels and Bax/Bcl-2 ratios decreased, and the ratio of phosphorylated connexin 43 (phospho-Cx43) to total Cx43 increased in infarcted tissues compared with the non-infarcted area (p < 0.05). Pinocembrin exhibited cardioprotective effects during I/R, evidenced by improved cardiac function, fewer arrhythmias, and smaller infarcts in treated hearts than in controls. These benefits may be due to pinocembrin's antiapoptotic and anti-oxidative stress effects and its ability to increase the phosphorylation of Cx43 in ischemic myocardium.

Pleiotropic preconditioning-like cardioprotective effects of hypolipidemic drugs in acute ischemia-reperfusion in normal and hypertensive rats.

Although pleiotropy, which is defined as multiple effects derived from a single gene, was recognized many years ago, and considerable progress has since been achieved in this field, it is not very clear how much this feature of a drug is clinically relevant. During the last decade, beneficial pleiotropic effects from hypolipidemic drugs (as in, effects that are different from the primary ones) have been associated with reduction of cardiovascular risk. As with statins, the agonists of peroxisome proliferator-activated receptors (PPARs), niacin and fibrates, have been suggested to exhibit pleiotropic activity that could significantly modify the outcome of a cardiovascular ailment. This review examines findings demonstrating the impacts of treatment with hypolipidemic drugs on cardiac response to ischemia in a setting of acute ischemia-reperfusion, in relation to PPAR activation. Specifically, it addresses the issue of susceptibility to ischemia, with particular regard to the preconditioning-like cardioprotection conferred by hypolipidemic drugs, as well as the potential molecular mechanisms behind this cardioprotection. Finally, the involvement of PPAR activation in the mechanisms of non-metabolic cardioprotective effects from hypolipidemic drugs, and their effects on normal and pathologically altered myocardium (in the hearts of hypertensive rats) is also discussed.

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.

Selective inhibition of the master regulator transcription factor Egr-1 with catalytic oligonucleotides reduces myocardial injury and improves left ventricular systolic function in a preclinical model of myocardial infarction.

BACKGROUND: Egr-1 is implicated in the pathogenesis of myocardial ischemia-reperfusion injury. The aim of this study was to ascertain the effectiveness of intracoronary delivery of DNAzyme targeting the transcription factor Egr-1 at reperfusion following experimental myocardial ischemia. METHODS AND RESULTS: Functional DNAzyme targeting Egr-1 or a size-matched scrambled control were delivered via the intracoronary route immediately on reperfusion after 60 minutes' balloon occlusion of the left anterior descending coronary artery in a pig model of myocardial I/R injury (n=7 per treatment group). Heart function and extent of myocardial infarction were determined following intervention by echocardiography and cardiac magnetic resonance imaging, respectively. Hearts were removed and examined for molecular and histological markers of inflammation and apoptosis. Administration of functional DNAzyme led to an overall decrease in the expression of inflammatory markers including intracellular adhesion molecule-1, tissue factor, and complement 3, with associated decreases in the extent of neutrophil infiltration, oxidative damage, and subsequent apoptosis within the infarct border zone. Functional significance was indicated by an increase in salvaged left ventricular myocardium (P=0.012), ejection fraction (P=0.002), and fractional area change (P=0.039) in the functional DNAzyme-treated group compared with the control. CONCLUSIONS: Egr-1 silencing through intracoronary delivery of a targeting DNAzyme at the time of reperfusion following acute myocardial ischemia decreases myocardial inflammation and apoptosis leading to improved cardiac function.