scholarly journals STAT subtype specificity and ischemic preconditioning in mice: is STAT-3 enough?

2011 ◽  
Vol 300 (2) ◽  
pp. H522-H526 ◽  
Author(s):  
Michael D. Goodman ◽  
Sheryl E. Koch ◽  
Muhammad R. Afzal ◽  
Karyn L. Butler
Keyword(s):  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Contractile Function ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Cardiac Performance ◽  
Subtype Specificity ◽  
Developed Pressure ◽  
Perfused Hearts

The role of other STAT subtypes in conferring ischemic tolerance is unclear. We hypothesized that in STAT-3 deletion alternative STAT subtypes would protect myocardial function against ischemia-reperfusion injury. Wild-type (WT) male C57BL/6 mice or mice with cardiomyocyte STAT-3 knockout (KO) underwent baseline echocardiography. Langendorff-perfused hearts underwent ischemic preconditioning (IPC) or no IPC before ischemia-reperfusion. Following ex vivo perfusion, hearts were analyzed for STAT-5 and -6 phosphorylation by Western blot analysis of nuclear fractions. Echocardiography and postequilibration cardiac performance revealed no differences in cardiac function between WT and KO hearts. Phosphorylated STAT-5 and -6 expression was similar in WT and KO hearts before perfusion. Contractile function in WT and KO hearts was significantly impaired following ischemia-reperfusion in the absence of IPC. In WT hearts, IPC significantly improved the recovery of the maximum first derivative of developed pressure (+dP/d tmax) compared with that in hearts without IPC. IPC more effectively improved end-reperfusion dP/d tmax in WT hearts compared with KO hearts. Preconditioned and nonpreconditioned KO hearts exhibited increased phosphorylated STAT-5 and -6 expression compared with WT hearts. The increased subtype activation did not improve the efficacy of IPC in KO hearts. In conclusion, baseline cardiac performance is preserved in hearts with cardiac-restricted STAT-3 deletion. STAT-3 deletion attenuates preconditioning and is not associated with a compensatory upregulation of STAT-5 and -6 subtypes. The activation of STAT-5 and -6 in KO hearts following ischemic challenge does not provide functional compensation for the loss of STAT-3. JAK-STAT signaling via STAT-3 is essential for effective IPC.

scholarly journals The role of ischemic preconditioning and pentoxifylline in intestinal ischemia/reperfusion injury of rats

2017 ◽  
Vol 32 (7) ◽  
pp. 559-567 ◽  
Author(s):  
Teresinha Regina Ribeiro de Oliveira ◽  
Geraldo Ferreira de Oliveira ◽  
Ricardo Santos Simões ◽  
Eduardo Hiroshi Tikazawa ◽  
Hugo Pequeno Monteiro ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemic Preconditioning ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Intestinal Ischemia Reperfusion

scholarly journals Overexpression of A3 adenosine receptors decreases heart rate, preserves energetics, and protects ischemic hearts

2002 ◽  
Vol 283 (4) ◽  
pp. H1562-H1568 ◽  
Author(s):  
Heather R. Cross ◽  
Elizabeth Murphy ◽  
Richard G. Black ◽  
John Auchampach ◽  
Charles Steenbergen
Keyword(s):  
Heart Rate ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Specific Inhibitor ◽  
Left Ventricular ◽  
Atp Depletion ◽  
Wild Type ◽  
Basal Heart Rate ◽  
Developed Pressure

To determine whether A3 adenosine receptor (A3AR) signaling modulates myocardial function, energetics, and cardioprotection, hearts from wild-type and A3AR-overexpressor mice were subjected to 20-min ischemia and 40-min reperfusion while 31P NMR spectra were acquired. Basal heart rate and left ventricular developed pressure (LVDP) were lower in A3AR-overexpressor hearts than wild-type hearts. Ischemic ATP depletion was delayed and postischemic recoveries of contractile function, ATP, and phosphocreatine were greater in A3AR-hearts. To determine the role of depressed heart rate and to confirm A3AR-specific signaling, hearts were paced at 480 beats/min with or without 60 nmol/l MRS-1220 (A3AR-specific inhibitor) and then subjected to ischemia-reperfusion. LVDP was similar in paced A3AR-overexpressor and paced wild-type hearts. Differences in ischemic ATP depletion and postischemic contractile and energetic dysfunction remained in paced A3AR-overexpressor hearts versus paced wild-type hearts but were abolished by MRS-1220. In summary, A3AR overexpression decreased basal heart rate and contractility, preserved ischemic ATP, and decreased postischemic dysfunction. Pacing abolished the decreased contractility but not the ATP preservation or cardioprotection. Therefore, A3AR overexpression results in cardioprotection via a specific A3AR effect, possibly involving preservation of ATP during ischemia.

Mechanisms of Erythropoietin-Mediated Cardioprotection during Ischemia-Reperfusion Injury: Role of Protein Kinase C Signaling.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2907-2907
Author(s):  
Murat O. Arcasoy ◽  
Paul Hanlon ◽  
Ping Fu ◽  
Charles Steenbergen ◽  
Elizabeth Murphy
Keyword(s):  
Protein Kinase ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Cardioprotective Effect ◽  
Isolated Perfused Heart ◽  
Perfused Heart ◽  
Biologic Effects

Abstract The biologic effects of erythropoietin (EPO) are mediated by its cellular receptor EPOR, a member of the cytokine receptor superfamily. EPOR expression in non-hematopoietic cells is associated with novel biologic effects for EPO in diverse organ systems. We recently demonstrated functional EPOR expression in adult rat cardiac myocytes and found that recombinant EPO exerts a rapid cardioprotective effect during ischemia-reperfusion injury of the isolated, perfused heart. Here we investigated the mechanisms of the cardioprotective effect of EPO using Langendorff-perfused rat hearts while left-ventricular-developed pressure (LVDP) was measured continuously to assess contractile function. Hearts were treated directly with EPO in the presence or absence of inhibitors of specific signal transduction pathways prior to normothermic global ischemia followed by reperfusion. Post-ischemic recovery of contractile function was determined by measuring LVDP at the end of reperfusion and expressed as a percentage of the baseline pre-treatment measurement. We investigated EPO-mediated activation of signal transduction pathways in the isolated, perfused heart and observed phosphorylation of p44/p42 MAP kinases ERK 1/2 (Thr202/Tyr204) and protein kinase B/Akt (Ser473), a downstream target of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Furthermore, EPO treatment of the isolated, perfused heart was associated with translocation of protein kinase C (PKC) ε and δ isoforms to the membrane fraction. We investigated the role of specific signaling pathways in EPO-mediated cardioprotection by employing inhibitors targeting PI3K, PKC and MAP kinase kinase (MEK1). PI3K inhibitors LY294002 and wortmannin attenuated EPO-induced phosphorylation of Akt but had no effect on EPO-mediated cardioprotection. MEK1 inhibitor U0126 had no effect on EPO-mediated cardioprotection. The PKC catalytic inhibitor chelerythrine (chel) significantly inhibited EPO-mediated improvement in post-ischemic recovery of LVDP (figure 1). Hearts pre-treated with EPO exhibited significantly improved post-ischemic recovery of LVDP compared to control hearts (mean±SE: 72±3 in EPO-treated versus 35±3% in control hearts, P<0.05 by ANOVA and Bonferroni post-hoc test, n=10 experiments each group) and the protective effect of EPO was significantly inhibited in chel-treated hearts (52±4% in EPO+chel versus 72±3% in EPO-treated hearts, P<0.05, n=10). As a control, treatment of the hearts with chelerythrine alone had no significant effect on LVDP (49±4%) compared to control hearts. These data demonstrate that EPO-mediated activation of the PKC signaling pathway is required for the cardioprotective effect of EPO during ischemia-reperfusion injury. Figure Figure

Ischemic preconditioning modulates ischemia-reperfusion injury in the rat lung: Role of adenosine receptors

2007 ◽  
Vol 556 (1-3) ◽  
pp. 144-150 ◽  
Author(s):  
Gülüzar Yıldız ◽  
Abdullah T. Demiryürek ◽  
Bülent Gümüşel ◽  
Howard Lippton
Keyword(s):  
Reperfusion Injury ◽  
Ischemic Preconditioning ◽  
Adenosine Receptors ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Rat Lung

Abstract 494: P21 Plays a Protective Role Against Renal Ischemia Reperfusion Injury and is an Essential Factor for Ischemic Preconditioning

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Satoshi Nishioka ◽  
Daisuke Nakano ◽  
Kento Kitada ◽  
Hiroyuki Ohosaki ◽  
Tadashi Sofue ◽  
...  
Keyword(s):  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Protective Role ◽  
Renal Ischemia ◽  
Histological Changes ◽  
Sham Surgery ◽  
Life Threatening

Background: We previously reported that various pathological conditions including high blood pressure increase p21 expression in the kidney; however, the functional importance of renal p21 up-regulation has not been clarified yet. In the present study, we evaluated the role of p21 in acute kidney injury, a life-threatening disease that can occur independently of the pathological background of patients (whether renal p21 is up-regulated or not). Methods and Results: The mice lacking functional p21 (p21-KO, n=9) and its wild-type control (WT, n=7) underwent a 45-min renal ischemia followed by a 24-h reperfusion (I/R). I/R significantly increased both mRNA expression and nuclear immunoreactivity of p21 in the kidney of WT compared with sham surgery (p21/β-actin, 1.28±0.23 vs. 0.57±0.15, respectively, P<0.05). I/R injury analyzed by blood urea nitrogen (BUN) and kidney histological changes were exacerbated in p21-KO mice (BUN: WT; 103.8±4.6 mg/dL, p21-KO; 127.7±5.2 mg/dL, P<0.05). The results suggest that p21 plays a protective role against I/R injury. Therefore, we next examined whether p21 is also associated with the protective effect of ischemic preconditioning (IPC), which is an established method of attenuating the I/R injury. IPC (4 sets of a 5-min ischemia and a 5-min reperfusion) clearly improved the I/R injury in WT (BUN: sham; 87.7±22.0 mg/dL, IPC; 39.0±2.3 mg/dL, n=3 and n=7, respectively, P<0.05), whereas there was no difference in the I/R injury in p21-KO mice (BUN: sham; 136.5±13.6 mg/dL, IPC; 127.9±6.9 mg/dL, n=5 and n=8, respectively). IPC increased the renal expression of p21 prior to I/R compared with sham surgery (p21/β-actin: 1.07±0.08 vs. 0.26±0.05 fold, respectively, P<0.05). Conclusion: Renal p21 plays a protective role against I/R injury and is necessary for the beneficial effect of renal IPC.

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