Faculty Opinions recommendation of Vardenafil: a novel type 5 phosphodiesterase inhibitor reduces myocardial infarct size following ischemia/reperfusion injury via opening of mitochondrial K(ATP) channels in rabbits.

2006 ◽  
Author(s):  
Andreas Deussen
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Phosphodiesterase Inhibitor ◽  
Myocardial Infarct Size

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.

Abstract 115: Post-ischemic Estrogen Administration Protects the Myocardium Against Ischemia/Reperfusion Injury by Reducing Mitochondrial Protein Ubiquitination, Acetylation and Calpain10 Levels and Inhibition of the mPTP Opening via GPER1 Activation

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Yansheng Feng ◽  
Ngonidzashe Benson Madungwe ◽  
Mohammad Enamul Kabir ◽  
Jean C. Bopassa
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Mitochondrial Protein ◽  
Myocardial Infarct Size ◽  
Protein Acetylation ◽  
Protein Ubiquitination ◽  
Mptp Opening

Introduction: We recently found in isolated perfused hearts that acute pre-ischemic estrogen-induced cardioprotection against ischemia/reperfusion injury is mainly mediated via G protein-coupled estrogen receptor1 (GPER1) activation but not through classical estrogen receptors: alpha (ERα) and beta (ERβ). Hypothesis: We investigated whether acute post-ischemic estrogen (PI-E2) treatment can also induce cardioprotective effects via GPER1 activation in the intact animal subjected to ischemia/reperfusion injury. Methods: Male and ovariectomized female Sprague-Dawley rats were anesthetized with ketamine (80 mg/kg i.p.) and xylazine (8 mg/kg i.p.). Hearts were subjected to 35 min of the left anterior descending (LAD) artery occlusion, followed by 180 min reperfusion. An E2 bolus (50 mg/kg body weight) or PBS (same volume) was applied via the femoral vein 5 min before reperfusion and a GPER1 antagonist, G15, was given 10 min before E2. Area at risk (AAR) was identified using Evans Blue dye and myocardial infarct size assessed by TTC staining method. Mitochondria calcium retention capacity (CRC) required to induce mitochondrial permeability transition pore (mPTP) opening was assessed after 10 min reperfusion. Expression of ubiquitinated, acetylated, as well as calpains 1 and 10 proteins was measured by Western Blot in mitochondrial and cytosolic fractions. Results: We found that PI-E2 treatment reduced myocardial infarct size normalized to the AAR or the whole LV and improved mitochondrial CRC. PI-E2 treatment reduced mitochondrial protein acetylation, ubiquitination, and decreased calpain10 levels in mitochondrial but not in cytosolic fractions as compared to control, respectively. Interestingly, all these effects of E2 were abolished by addition of G15. Conclusion: Acute post-ischemic GPER1 activation by E2 induces cardioprotection against ischemia/reperfusion injury. PI-E2 effects through GPER1 involve the reduction of the levels of mitochondrial protein acetylation, ubiquitination, and calpain10. These PI-E2-GPER1 effects lead to inhibition of the mPTP opening.

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