Comparison of Pyrroloquinoline Quinone and/or Metoprolol on Myocardial Infarct Size and Mitochondrial Damage in a Rat Model of Ischemia/Reperfusion Injury

2006 ◽  
Vol 11 (2) ◽  
pp. 119-128 ◽  
Author(s):  
Bo-qing Zhu ◽  
Ursula Simonis ◽  
Gary Cecchini ◽  
Hui-zhong Zhou ◽  
Luyi Li ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Rat Model ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Pyrroloquinoline Quinone ◽  
Mitochondrial Damage ◽  
Myocardial Infarct Size

Abstract 17348: Necrostatin 7 Limits Myocardial Infarct Size and Reduces Cardiac Remodeling After Permanent Coronary Occlusion in Rats

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Yuri Dmitriev ◽  
Sarkis Minasian ◽  
Anna Dracheva ◽  
Andrey Karpov ◽  
Svetlana Chefu ◽  
...  
Keyword(s):  
Infarct Size ◽  
Rat Model ◽  
Coronary Occlusion ◽  
Ventricular Remodeling ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Morphological Characteristics ◽  
Left Ventricular ◽  
Myocardial Infarct Size

Background: Reduction of irreversible myocardial ischemia-reperfusion injury (IRI) remains important. One of the promising strategies aimed at myocardial IRI alleviation is modulation of programmed cell death (PCD) pathways. PCD mode displaying morphological characteristics of necrosis, and amenable to pharmacological manipulation is referred to as necroptosis. Necroptosis inhibitor necrostatin-1 has been shown to exert cardio- and neuroprotective effects. In the present work, the effect of necrostatin-7 (Nec-7) on myocardial injury in the rat model of permanent coronary occlusion was studied. Methods: Male Wistar rats (n = 19) were anesthetized with pentobarbital. The animals were subjected to permanent coronary occlusion (PCO) and intraperitoneal (i.p.) Nec-7 administration 1 h prior to PCO at a dose of 14.5 mg/kg in dimethyl sulfoxide (DMSO) or DMSO alone at a dose of 3.1 g/kg. Control rats were treated with saline. Three weeks after PCO, serum levels of NT-proBNP were measured, and histological outcomes were assessed. The infarct size (IS, %) and infarct length (IL, mm) were analyzed morphometrically. Results: DMSO caused significant reduction in serum NT-proBNP level vs. Control (0.3 ± 0.19 vs. 0.5 ± 0.22 ng/ml, p = 0.001), while Nec-7 further decreased NT-proBNP level in comparison with DMSO (0.2 ± 0.14 ng/ml, p = 0.008 vs. DMSO). Compared with Control, DMSO reduced adverse left ventricular remodeling, as evidenced by reduction in IS (16.0 ± 2.92 and 12.9 ± 1.72%, p = 0.015) and IL (6.2 ± 0.89 and 3.8 ± 0.35 mm, p = 0.008). Nec-7 treatment resulted in additional reduction of both IS and IL vs. DMSO group (9.0 ± 4.91 % and 2.9 ± 1.62 mm, respectively; p = 0.013 and p = 0.011 vs. DMSO, respectively). Conclusion: Nec-7 has cardioprotective properties, reducing myocardial wall stress and myocardial remodeling in the rat model of myocardial infarction.

Effects of selective inhibition of cytochrome P-450 ω-hydroxylases and ischemic preconditioning in myocardial protection

2006 ◽  
Vol 290 (2) ◽  
pp. H500-H505 ◽  
Author(s):  
Kasem Nithipatikom ◽  
Michael P. Endsley ◽  
Jeannine M. Moore ◽  
Marilyn A. Isbell ◽  
John R. Falck ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Canine Heart ◽  
Area At Risk ◽  
Cytochrome P 450

Cytochrome P-450 (CYP) ω-hydroxylases and their arachidonic acid (AA) metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), produce a detrimental effect on ischemia-reperfusion injury in canine hearts, and the inhibition of CYP ω-hydroxylases markedly reduces myocardial infarct size expressed as a percentage of the area at risk (IS/AAR, %). In this study, we demonstrated that a specific CYP ω-hydroxylase inhibitor, N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), markedly reduced 20-HETE production during ischemia-reperfusion and reduced myocardial infarct size compared with control [19.5 ± 1.0% (control), 9.6 ± 1.5% (0.40 mg/kg DDMS), 4.0 ± 2.0% (0.81 mg/kg DDMS), P < 0.01]. In addition, 20-hydroxyeicosa-6( Z),15( Z)-dienoic acid (20-HEDE, a putative 20-HETE antagonist) significantly reduced myocardial infarct size from control [10.3 ± 1.3% (0.032 mg/kg 20-HEDE) and 5.9 ± 1.9% (0.064 mg/kg 20-HEDE), P < 0.05]. We further demonstrated that one 5-min period of ischemic preconditioning (IPC) reduced infarct size to a similar extent as that observed with the high doses of DDMS and 20-HEDE, and the higher dose of DDMS given simultaneously with IPC augmented the infarct size reduction [9.9 ± 2.8% (IPC) to 2.5 ± 1.4% (0.81 mg/kg DDMS), P < 0.05] to a greater degree than that observed with either treatment alone. These results suggest an important negative role for endogenous CYP ω-hydroxylases and their product, 20-HETE, to exacerbate myocardial injury in canine myocardium. Furthermore, for the first time, this study demonstrates that the effect of IPC and the inhibition of CYP ω-hydroxylase synthesis (DDMS) or its actions (20-HEDE) may have additive effects in protecting the canine heart from ischemia-reperfusion injury.

Abstract 094: Antithrombin Exerts a Cardioprotective Effect against Myocardial Ischemic/reperfusion Injury through Induction of Prostacyclin and Inhibition of NF-kB Signaling

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ji Li ◽  
Jingying Wang ◽  
Yanqing Wang ◽  
Jinli Wang ◽  
Junjie Gao ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Therapeutic Potential ◽  
Anticoagulant Activity ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Acute Injury ◽  
Drug Candidate ◽  
Myocardial Infarct Size

Antithrombin (AT) is a plasma serpin inhibitor that regulates the proteolytic activity of procoagulant proteases of the clotting cascade. In addition to its anticoagulant activity, AT also possesses potent antiinflammatory and antiangiogenic properties. In this study, we investigated the antiinflammatory activity of wild-type AT (AT-WT) and a reactive center loop mutant of AT (AT-RCL) not capable of inhibiting thrombin in a mouse model of ischemia/reperfusion injury in which the left anterior descending coronary artery (LAD) was occluded and released then. The results demonstrate that AT markedly reduces the myocardial infarct size (p<0.05 vs. vehicle) by a mechanism that is independent of its anticoagulant activity. Thus, the AT-RCL mutant, lacking any detectable reactivity with thrombin, attenuated myocardial infarct size to the same extent as the AT-WT in the acute injury model. Further studies revealed that AT binds to vascular heparan sulfate proteoglycans via its heparin-binding domain to exert its protective activity as evidenced by the therapeutic AT-binding pentasaccharide fragment of heparin (fondaparinux) abrogating the cardioprotective activity of AT. We further demonstrate that AT up-regulates the production of prostacyclin in myocardial tissues (p<0.05 vs. vehicle) and inhibits the production of proinflammatory cytokines TNF-α and IL-6 (p<0.05 vs. vehicle) in vivo by attenuating the ischemia/reperfusion-induced JNK and NF-κB signaling pathways. These results suggest that AT, through its antiinflammatory signaling effect, may have therapeutic potential for reducing cardiac ischemia/reperfusion injury and that a normal cardioprotective activity for the AT-RCL variant renders it a superior drug candidate if bleeding becomes a concern in the treatment.

Abstract 2323: Protection of Diabetic Heart with Glutaredoxin Gene Therapy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Istvan Lekli ◽  
Subhendu Mukherjee ◽  
Diptarka Ray ◽  
Narasimman Gurusamy ◽  
Dipak Das
Keyword(s):  
Gene Therapy ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Cardiomyocyte Apoptosis ◽  
Heme Oxygenase 1 ◽  
Myocardial Infarct Size ◽  
Empty Vector

Glutaredoxin-1 [Grx1], a redox regulator of thioredoxin superfamily has been implicated in myocardial ischemia reperfusion injury. Diabetes is a well-recognized cardiovascular risk factor. Grx1 has been shown to protect the heart from ischemia reperfusion induced injuries. The present study examined whether Grx1 gene therapy could render the diabetic hearts resistant to ischemia reperfusion injury. Diabetes was induced with streptozotocin, and after the diabetes was confirmed, male C57B1/J6 mice were assigned to one of the two groups and open heart surgery was performed. The mice received an intra-myocardial injection of 109 p.f.u. adenovirus encoding Grx1 or injected with empty vector or adenovirus with LacZ. Three days later, the animals were sacrificed and isolated hearts were subjected to 30 min ischemia followed by 2 hours of reperfusion. Ventricular function was examined, and myocardial infarct size and cardiomyocyte apoptosis were determined. Hemodynamic parameters of the Grx1 overexpressed hearts exhibited improved function compared to those treated with either empty vector or LacZ. Grx1 overexpressed hearts also exhibited reduced myocardial infarct size and cardiomyocyte apoptosis. We examined the protein level of ASK1 and the activation of its downstream target JNK, P38MAPK and the level of procaspase 3 as well as the activities of Akt, and c-Src. Grx1 gene therapy inhibited the phosphorylation of c-Src, as well as suppressed the activities of the ASK1 and JNK indicating a reduction of overall death signal. Grx1 overexpression restored the procaspase 3 level. Akt phosphorylation was significantly higher compared to control hearts. The expression of phase II enzyme heme oxygenase-1 was higher after GRX1 gene therapy. Interestingly thioredoxin (Trx)-1 and Trx-2 protein levels were also slightly higher after GRX-1 treatment. The results of this study indicate cardioprotection with Grx1 gene therapy in diabetic hearts as evidenced by improved post ischemic cardiac performance, reduction of myocardial infarct size and cardiomyocite apoptosis as well as significant reduction of ischemia-reperfusion induced death signal.

Abstract 289: Cardiac-Specific Ectonucleoside Triphosphate Diphosphohydrolase 1 Overexpression Affords Protection from Myocardial Infarction and Reperfusion Injury

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Zhaobin Xu ◽  
Debra G Wheeler ◽  
Shouvik D Mahamud ◽  
Karen M Dwyer ◽  
Simon C Robson ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Area At Risk ◽  
Tetrazolium Chloride ◽  
Myocardial Ischemia Reperfusion

Background: During myocardial stress, extracellular levels of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) increase. These extracellular ATP and ADP levels are modulated via hydrolysis by ectonucleoside triphosphate diphosphohydrolase 1 (ENTDP-1/CD39) to adenosine monophosphate (AMP) subsequently converted by ecto-5'-nucleotidase (CD73) to the anti-thrombotic, cardioprotective nucleoside, adenosine. Previous data demonstrated significantly smaller infarcts in mice globally overexpressing CD39. The current objective was to determine whether tissue specific overexpression of CD39 in the heart would reduce myocardial ischemia/reperfusion injury. Methods: Myocardial ischemia/reperfusion (I/R) injury was evaluated in transgenic mice overexpressing human CD39 driven by the α-MHC promoter. I/R injury was induced by ligation of the left anterior descending (LAD) artery for 60 min followed by 24 hours of reperfusion. Myocardial infarct size was determined by staining with triphenyl tetrazolium chloride (TTC) and the area-at-risk was delineated by perfusion with 5% Phthalo Blue. Results: Expression of CD39 in the heart tissue was confirmed by Western blot analysis. In response to 60 minutes of ischemia followed by 24 hours of reperfusion, α-MHC CD39-OE animals displayed a marked reduction in infarct size (WT: 31.68%±4.64 vs TG: 6.14%± 2.48, N=5/group, P<0.01), relative to wild-type controls (Figure). Conclusions: Overexpression of CD39 in cardiac tissue alone significantly attenuates myocardial ischemic injury.

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