scholarly journals Sex-related resistance to myocardial ischemia-reperfusion injury is associated with high constitutive ARC expression

2010 ◽  
Vol 298 (5) ◽  
pp. H1510-H1517 ◽  
Author(s):  
Wobbe Bouma ◽  
Mio Noma ◽  
Shinya Kanemoto ◽  
Muneaki Matsubara ◽  
Bradley G. Leshnower ◽  
...  
Keyword(s):  
Cell Death ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Apoptotic Cell Death ◽  
Cardiomyocyte Apoptosis ◽  
Myocardial Salvage ◽  
Area At Risk ◽  
Myocardial Area

The female sex has been associated with improved myocardial salvage after ischemia and reperfusion (I/R). Estrogen, specifically 17β-estradiol, has been demonstrated to mediate this phenomenon by limiting cardiomyocyte apoptosis. We sought to quantitatively assess the effect of sex, ovarian hormone loss, and I/R on myocardial Bax, Bcl-2, and apoptosis repressor with caspase recruitment domain (ARC) expression. Male ( n = 48), female ( n = 26), and oophorectomized female ( n = 20) rabbits underwent 30 min of regional ischemia and 3 h of reperfusion. The myocardial area at risk and infarct size were determined using a double-staining technique and planimetry. In situ oligo ligation was used to assess apoptotic cell death. Western blot analysis was used to determine proapoptotic (Bax) and antiapoptotic (Bcl-2 and ARC) protein levels in all three ischemic groups and, additionally, in three nonischemic groups. Infarct size (43.7 ± 3.2%) and apoptotic cell death (0.51 ± 0.10%) were significantly attenuated in females compared with males (56.4 ± 1.6%, P < 0.01, and 4.29 ± 0.95%, P < 0.01) and oophorectomized females (55.7 ± 3.4%, P < 0.05, and 4.36 ± 0.51%, P < 0.01). Females expressed significantly higher baseline ARC levels (3.62 ± 0.29) compared with males (1.78 ± 0.18, P < 0.01) and oophorectomized females (1.08 ± 0.26, P < 0.01). Males expressed a significantly higher baseline Bax-to-Bcl-2 ratio (4.32 ± 0.99) compared with females (0.65 ± 0.13, P < 0.01) and oophorectomized females (0.42 ± 0.10, P < 0.01). I/R significantly reduced Bax-to-Bcl-2 ratios in males. In all other groups, ARC levels and Bax-to-Bcl-2 ratios did not significantly change. These results support the conclusion that in females, endogenous estrogen limits I/R-induced cardiomyocyte apoptosis by producing a baseline antiapoptotic profile, which is associated with estrogen-dependent high constitutive myocardial ARC expression.

Verapamil Reduces Coronary Endothelium Damage and Cardiomyocyte Necrosis but not Apoptosis after Ischemia and Reperfusion: Ex Vivo Study in Rat Hearts

2002 ◽  
Vol 15 (3) ◽  
pp. 225-232 ◽  
Author(s):  
P. Di Napoli ◽  
A. A. Taccardi ◽  
A. Grilli ◽  
M. Felaco ◽  
L. Di Gioacchino ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Cardiomyocyte Apoptosis ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Heart Weight ◽  
Acute Administration ◽  
Rat Hearts

We tested the hypothesis of beneficial effects of the calcium-blocker verapamil in a model of ischemia-reperfusion, and investigated its effects against coronary microcirculation and cardiomyocyte apoptosis. Isolated working rat hearts were subjected to 15 min global ischemia and 22–180 min reperfusion in the presence or absence of verapamil (0.25 μM). We evaluated creatinephosphokinase (CK) in coronary effluent, heart weight changes, microvascular permeability (extravasation of fluoresceinelabeled albumin), ultrastructural alterations, and cardiomyocyte apoptosis (by 1.5% agarose gel electrophoresis and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling technique). In this model, 0.25 μM verapamil significantly reduced myocardial damage, CK release and vascular hyperpermeability, concomitant with a reduction in endothelial and cardiomyocyte lesions; on the contrary, 0.25 μM verapamil was unable to reduce cardiomyocyte apoptosis. In conclusion, in the absence of perfusing granulocytes, the acute administration of a pharmacologically relevant verapamil concentration reduces ischemia-reperfusion injury and prevents coronary endothelial cell and cardiomyocyte necrotic cell death but it is unable to reduce apoptotic cell death in isolated working rat hearts.

Abstract 217: Use of Magnetic Resonance Imaging Method For Quantification Of Myocardial Salvage In A Rat Model Of Ischemia-reperfusion Injury.

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Stuart M Grieve ◽  
Jawad Mazhar ◽  
Fraser Callaghan ◽  
Cindy Y Kok ◽  
Ravinay Bhindi ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Observer Variation ◽  
Myocardial Salvage ◽  
Imaging Method ◽  
Signal Loss ◽  
Current Standard ◽  
Area At Risk ◽  
Myocardial Area

Introduction: Quantification of myocardial “area-at-risk” (AAR) and infarct (MI) zone is critical for assessing novel therapies targeting myocardial ischemia-reperfusion (IR) injury. The current standard method involves perfusion with Evan’s Blue (EB), staining with TTC and manual slicing and analysis. We have developed an MRI method for quantifying MI and AAR in whole hearts which provides superior 3D resolution to the standard approach. Methods: Rats were given an IR injury, recovered for 24 hours then infused with Gd-DTPA via the tail vein. The coronary artery was then religated, and a solution containing both iron oxide microparticles and EB was infused. For comparison, hearts were then harvested and transversally sectioned for TTC staining. Some hearts were kept intact for MRI only analysis. Ex-vivo MRI T2* and T1 images were acquired on a 9.4T magnet. The AAR (red) was quantified by comparing the T2* signal loss in perfused regions (blue) and high T1-signal in infarcted zones (white) from Gd-DTPA retention. Results: MRI and EB/TTC measures on the same slice for both AAR and MI were highly correlated (r=0.92-0.94;p<0.05). 3D MRI acquisition and analysis of whole hearts reduced intra-observer variability, and automated segmentation and analysis further reduced inter-observer variation. Conclusion: This novel MRI technique allows precise assessment of infarct and AAR zones and is highly suited to automation of both analysis and acquisition. This method could remove the need for tissue slicing, and via a centralised MRI facility, could permit 3D digital analysis of hearts at high anatomical resolution, accessible for all laboratories already performing IR experiments.

Ischemic Preconditioning Prevents Apoptotic Cell Death and Necrosis in Early and Intermediate Phases of Liver Ischemia-Reperfusion Injury in Rats

2006 ◽  
Vol 19 (4) ◽  
pp. 229-236 ◽  
Author(s):  
Claudemiro Quireze ◽  
Edna Frasson de Souza Montero ◽  
Regina Maria Cubero Leitão ◽  
Yara Juliano ◽  
Djalma José Fagundes ◽  
...  
Keyword(s):  
Cell Death ◽  
Reperfusion Injury ◽  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Apoptotic Cell Death ◽  
Liver Ischemia ◽  
Intermediate Phases

PERP, a p53 proapoptotic target, mediates apoptotic cell death in renal ischemia

2009 ◽  
Vol 296 (4) ◽  
pp. F847-F858 ◽  
Author(s):  
Kurinji Singaravelu ◽  
Kishor Devalaraja-Narashimha ◽  
Brynn Lastovica ◽  
Babu J. Padanilam
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Ischemia Reperfusion Injury ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Suppressor Gene ◽  
Apoptotic Cell Death ◽  
Renal Ischemia ◽  
Dependent Manner ◽  
Apoptotic Pathways

The p53 tumor suppressor gene plays a crucial role in mediating apoptotic cell death in renal ischemia-reperfusion injury (IRI). To further elucidate the p53-dependent pathway, we investigated the role of the p53 apoptosis effector related to PMP-22 (PERP), an apoptosis-associated p53 transcriptional target. PERP mRNA and protein are highly induced in the outer medullary proximal tubular cells (PTC) of ischemic kidneys postreperfusion at 3, 12, and 24 h in a p53-dependent manner. In PTC, overexpression of PERP augmented the rate of apoptosis following hypoxia by inducing mitochondrial permeability and subsequent release of cytochrome c, apoptosis-inducing factor (AIF), and caspase 9 activation. In addition, silencing of the PERP gene with short hairpin RNA prevented apoptosis in hypoxia-mediated injury by precluding mitochondrial dysfunction and consequent cytochrome c and AIF translocation. These data suggest that PERP is a key effector of p53-mediated apoptotic pathways and is a potential therapeutic target for renal IRI.

Abstract 13879: Ischemic Postconditioning Confers Cardioprotection through Adiponectin-dependent Mitochondrial STAT3 Activation in Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Haobo Li ◽  
Michael G Irwin ◽  
Zhengyuan Xia
Keyword(s):  
Cell Injury ◽  
Troponin I ◽  
Ischemia Reperfusion Injury ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Cardiac Injury ◽  
Systolic Pressure ◽  
Gene Knockdown ◽  
Area At Risk ◽  
In Cells

Introduction: Signal transducer and activator of transcription 3 (STAT3) plays a key role in postconditioning (IPo) mediated protection against myocardial ischemia reperfusion injury, but the mechanism by which IPo activates STAT3 is unknown. Adiponectin (APN), a protein with anti-ischemic properties, activates STAT3. We hypothesized that IPo activates mitochondrial STAT3 (MitoSTAT3) via APN signaling. Methods and Results: Wild type (WT) and APN knockout (KO) mice were either sham operated or subjected to 30 min of coronary artery occlusion followed by 2 hours of reperfusion with or without IPo (3 cycles of 10 seconds reperfusion and 10 seconds reocclusion; n=8/group). At the end of reperfusion, KO mice exhibited more severe myocardial injury evidenced as increased infarct size (% of area at risk) 49.2±2.0 vs WT 39.4±3.5, P <0.01; plasma troponin I (ng/ml): KO 72.8±7.6 vs WT 45.7±4.0, P <0.01; worse cardiac function (lower dP/dt max and end-systolic pressure-volume relation, P <0.05); more severely impaired mitochondrial function (reductions in complex IV and complex V protein expression) and more severe reduction of MitoSTAT3 phosphorylation (activation) at site Ser727, P <0.01. IPo significantly attenuated post-ischemic cardiac injury and dysfunction with a concomitant increase in phosphorylated MitoSTAT3 and attenuation of mitochondrial dysfunction in WT (all P <0.05) but not in KO mice. In cultured cardiac H9C2 cells, hypoxic postconditioning (HPo, 3 cycles of 5 min hypoxia and 5 min reoxygenation) significantly attenuated hypoxia/reoxygenation (HR, 3 hours hypoxia/3 hours reoxygenation) induced cell injury (increased apoptotic cell death as % of HR): HR 100.2±0.4 vs HPo 78.2±4.8, P <0.05) and reduced mitochondrial transmembrane potential (% total cells, HR 37.2±4.9 vs HPo 23.5±3.7, P <0.01). APN, adiponectin receptor 1 (AdipoR1), or STAT3 gene knockdown but not AdipoR2 gene knockdown, respectively, abolished HPo cellular protection (all P <0.05 vs. HPo). APN supplementation (10μg/ml) restored HPo protection in cells with APN knockdown but not in cells with AdipoR1or STAT3 gene knockdown. Conclusion: Adiponectin and AdipoR1 signaling are required for IPo to activate myocardial mitochondrial STAT3 to confer cardioprotection.

Abstract 212: Cd4+ T-cell Activation By T-cell Receptor Engagement Contributes To Myocardial Ischemia-reperfusion Injury

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ulrich Hofmann ◽  
Denise Mathes ◽  
Johannes Weirather ◽  
Niklas Beyersdorf ◽  
Thomas Kerkau ◽  
...  
Keyword(s):  
At Risk ◽  
T Cells ◽  
T Cell ◽  
Infarct Size ◽  
T Cell Receptor ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cell Receptor ◽  
Area At Risk ◽  
Infarct Area

Background: We have recently shown that CD4 + but not CD8 + T-cells contribute to ischemia-reperfusion injury of the myocardium. We therefore hypothesized that CD4 + T-cells become activated by autoantigen recognition via their T-cell receptor during reperfusion. Methods and Results: Infarct size as percent of the area-at-risk was determined by combined Evans` blue and triphenyltetrazolium (TTC) staining after 30 minutes of in vivo ischemia followed by 24 hours reperfusion in mice. After 24 hours of reperfusion there was a significantly increased population of CD4 + T-cells which expressed the surface protein CD40L in comparison to sham operated mice [n≥7; p<0.05; WT 10.8 ± 0.2% vs. sham 6.4 ± 0.5%]. CD40L is typically expressed in T-cells activated by T-cell receptor engagement. OT-II mice carry a transgenic T-cell receptor with specificity for an ovalbumin-derived peptide. These mice have a limited T-cell receptor repertoire, dominated by specificity for the irrelevant antigen ovalbumin. After 30 minutes of ischemia and 24 hours of reperfusion OT-II mice showed significantly reduction in infarct size [n≥4; p= 0.02; infarct/area at risk: OTII mice 38.9 ± 2.4% vs. WT mice 63.7 ± 6.6 % ]. Administration of a CD40L blocking antibody to wildtype mice also reduced infarct size when compared to administration of isotype-matched antibodies [n≥6; p = 0.03; infarct/ area at risk: anti-CD154 treatment 60.4 ± 3.4% vs. control 75.3 ± 4.1%]. CD4 + CD25 + Foxp3 + T-cells (natural T-regulatory cells) have a low activation threshold and constitute a T-cell subset with reactivity against autoantigens. Depletion of these cells by diphtheria-toxin application in a mouse model expressing the diphtheria-toxin receptor under the Foxp3 promotor also resulted in a significant reduction of infarct size when compared to diphtheria-toxin treated wildtype mice [n≥4; p=0.03; infarct/ area at risk: T reg -depleted DEREG mice 51.9± 3% vs. WT littermates 72.3± 2%]. Conclusion: Our results indicate that CD4 + T-cells that have been activated by an MHC class II/ T-cell receptor dependent mechanism, presumably by autoantigen recognition, contribute to myocardial ischemia-reperfusion injury.

Abstract 300: Topical Application of IcyHot Reduces Myocardial Infarct Size in Rodents by a TRPA1-dependent Mechanism

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Yun Wu ◽  
Yao Lu ◽  
Eric R Gross
Keyword(s):  
Infarct Size ◽  
Transient Receptor Potential ◽  
Ischemia Reperfusion Injury ◽  
Calcium Influx ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Myocardial Infarct Size ◽  
Sprague Dawley ◽  
Area At Risk ◽  
Reactive Aldehydes

Toxic reactive aldehydes are formed during ischemia-reperfusion. The ion channel transient receptor potential ankryin 1 (TRPA1) is irreversibly modified by reactive aldehydes which can cause calcium influx and cell death. Here we tested whether topically applied creams containing a reversible TRPA1 agonist could reduce myocardial infarct size. Male Sprague-Dawley rats 8-10 weeks age were subjected to an in vivo myocardial ischemia-reperfusion model of 30 minutes of left anterior descending (LAD) coronary artery ischemia followed by 2 hours reperfusion. Prior to ischemia, rats were untreated or had 1g of cream applied to the abdomen. The creams tested were IcyHot, Bengay, Tiger Balm, or preparation H (Fig. 1A). Hearts were negatively stained for the area at risk and the infarct size was determined by using TTC staining (Fig. 1B). A subset of rodents prior to receiving IcyHot also received an intravenous bolus of the TRPA1 antagonist TCS-5861528 (1mg/kg) or AP-18 (1mg/kg). Interestingly, both IcyHot and Bengay reduced myocardial infarct size compared to untreated rodents (Fig. 1C and 1D IcyHot: 41±3%*, Bengay: 50±2%* versus control 62±1%, n=6/group, *P<0.001). Both preparation H and Tiger Balm failed to reduce myocardial infarct size (Tiger Balm: 63±2%, preparation H 59±2%). Giving a TRPA1 antagonist prior to IcyHot also blocked the reduction in infarct size. Our additional data also indicates the methyl salicylate (mint) in IcyHot and Bengay is the agent that limits myocardial infarct size. Since IcyHot and Bengay are safely used by humans, targeting TRPA1 by using products such as these could be quickly translatable and widely used to reduce ischemia-reperfusion injury.

scholarly journals Identification and Characterization of NTB451 as a Potential Inhibitor of Necroptosis

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2884 ◽  
Author(s):  
Eun-Jung In ◽  
Yuno Lee ◽  
Sushruta Koppula ◽  
Tae-Yeon Kim ◽  
Jun-Hyuk Han ◽  
...  
Keyword(s):  
Cell Death ◽  
Md Simulation ◽  
Ischemia Reperfusion Injury ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Direct Interaction ◽  
Inhibitory Effect ◽  
Therapeutic Implications ◽  
Pathological Conditions ◽  
Tnf Α

Necroptosis, or caspase-independent programmed cell death, is known to be involved in various pathological conditions, such as ischemia/reperfusion injury, myocardial infarction, atherosclerosis, and inflammatory bowel diseases. Although several inhibitors of necroptosis have been identified, none of them are currently in clinical use. In the present study, we identified a new compound, 4-({[5-(4-aminophenyl)-4-ethyl-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-N-(1,3-thiazol-2-yl) benzamide (NTB451), with significant inhibitory activity on the necroptosis induced by various triggers, such as tumor necrosis factor-α (TNF-α) and toll-like receptor (TLR) agonists. Mechanistic studies revealed that NTB451 inhibited phosphorylation and oligomerization of mixed lineage kinase domain like (MLKL), and this activity was linked to its inhibitory effect on the formation of the receptor interacting serine/threonine-protein kinase 1 (RIPK1)-RIPK3 complex. Small interfering RNA (siRNA)-mediated RIPK1 knockdown, drug affinity responsive target stability assay, and molecular dynamics (MD) simulation study illustrated that RIPK1 is a specific target of NTB451. Moreover, MD simulation showed a direct interaction of NTB451 and RIPK1. Further experiments to ensure that the inhibitory effect of NTB451 was restricted to necroptosis and NTB451 had no effect on nuclear factor-κB (NF-κB) activation or apoptotic cell death upon triggering with TNF-α were also performed. Considering the data obtained, our study confirmed the potential of NTB451 as a new necroptosis inhibitor, suggesting its therapeutic implications for pathological conditions induced by necroptotic cell death.

Sign in / Sign up

Export Citation Format

Share Document