Acute adenosine preconditioning is mediated by p38 MAPK activation in discrete subcellular compartments

2005 ◽  
Vol 288 (3) ◽  
pp. H1359-H1366 ◽  
Author(s):  
Cherry Ballard-Croft ◽  
Gentian Kristo ◽  
Yukihiro Yoshimura ◽  
Easton Reid ◽  
Byron J. Keith ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Adenosine Receptor ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fraction ◽  
Control Group ◽  
Mapk Activation ◽  
Subcellular Compartments ◽  
Sb 203580

Although acute adenosine preconditioning (PC) is well established, the signaling pathways mediating this cardioprotection remain unclear. Because adenosine receptor agonists activate p38 MAPK and this kinase has been implicated in ischemic and pharmacological PC, the purpose of this study was to determine the role of p38 MAPK in acute adenosine receptor PC. The role of p38 MAPK activation in discrete subcellular compartments during ischemia-reperfusion was also determined. The following groups were used in an in vivo rat ischemia-reperfusion model: 1) control (10% DMSO iv), 2) the A1/A2a adenosine receptor AMP-579 (50 μg/kg iv), 3) AMP-579 + the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 μg/kg iv), 4) AMP-579 + the p38 MAPK inhibitor SB-203580 (1 mg/kg iv), and 5) SB-203580 alone. p38 MAPK activation was measured by Western blot analysis in cytosolic, mitochondrial, membrane, and nuclear/myofilament fractions obtained from hearts at preischemic, ischemic, and reperfusion time points. A significant reduction in infarct size was observed with AMP-579 PC, an effect blocked by DPCPX or SB-203580 pretreatment. AMP-579 treatment was associated with a significant increase in p38 MAPK activation in the nuclear/myofilament fraction before ischemia, whereas no activation of this kinase occurred during ischemia or reperfusion. In contrast, p38 MAPK was activated in the mitochondrial fraction by ischemia and in the cytosolic, mitochondrial, and membrane fractions by reperfusion in the control group. SB-203580 blocked the AMP-579-induced increase in phosphorylation of the downstream p38 substrate activating transcription factor-2. These results suggest a role for p38 MAPK activation in discrete subcellular compartments in acute adenosine A1 receptor PC.

scholarly journals Role of Mitogen-Activated Protein Kinases in Myocardial Ischemia-Reperfusion Injury during Heart Transplantation

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Giuseppe Vassalli ◽  
Giuseppina Milano ◽  
Tiziano Moccetti
Keyword(s):  
Heart Transplantation ◽  
Organ Transplantation ◽  
P38 Mapk ◽  
Cold Storage ◽  
Organ Procurement ◽  
Ischemia Reperfusion ◽  
Solid Organ ◽  
Mapk Activation ◽  
Mitogen Activated Protein

In solid organ transplantation, ischemia/reperfusion (IR) injury during organ procurement, storage and reperfusion is an unavoidable detrimental event for the graft, as it amplifies graft inflammation and rejection. Intracellular mitogen-activated protein kinase (MAPK) signaling pathways regulate inflammation and cell survival during IR injury. The four best-characterized MAPK subfamilies are the c-Jun NH2-terminal kinase (JNK), extracellular signal- regulated kinase-1/2 (ERK1/2), p38 MAPK, and big MAPK-1 (BMK1/ERK5). Here, we review the role of MAPK activation during myocardial IR injury as it occurs during heart transplantation. Most of our current knowledge regarding MAPK activation and cardioprotection comes from studies of preconditioning and postconditioning in nontransplanted hearts. JNK and p38 MAPK activation contributes to myocardial IR injury after prolonged hypothermic storage. p38 MAPK inhibition improves cardiac function after cold storage, rewarming and reperfusion. Small-molecule p38 MAPK inhibitors have been tested clinically in patients with chronic inflammatory diseases, but not in transplanted patients, so far. Organ transplantation offers the opportunity of starting a preconditioning treatment before organ procurement or during cold storage, thus modulating early events in IR injury. Future studies will need to evaluate combined strategies including p38 MAPK and/or JNK inhibition, ERK1/2 activation, pre- or postconditioning protocols, new storage solutions, and gentle reperfusion.

LOX-1 inhibition in myocardial ischemia-reperfusion injury: modulation of MMP-1 and inflammation

2002 ◽  
Vol 283 (5) ◽  
pp. H1795-H1801 ◽  
Author(s):  
Dayuan Li ◽  
Victor Williams ◽  
Ling Liu ◽  
Hongjiang Chen ◽  
Tatsuya Sawamura ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
P38 Mapk ◽  
Adhesion Molecule ◽  
Ischemia Reperfusion ◽  
Control Group ◽  
Adhesion Molecule Expression ◽  
Sham Control ◽  
Mapk Activation ◽  
Sham Control Group ◽  
Myocardial Ischemia Reperfusion

A recently identified lectin-like oxidized low-density lipoprotein receptor (LOX-1) mediates endothelial cell injury and facilitates inflammatory cell adhesion. We studied the role of LOX-1 in myocardial ischemia-reperfusion (I/R) injury. Anesthetized Sprague-Dawley rats were subjected to 60 min of left coronary artery (LCA) ligation, followed by 60 min of reperfusion. Rats were treated with saline, LOX-1 blocking antibody JXT21 (10 mg/kg), or nonspecific anti-goat IgG (10 mg/kg) before I/R. Ten other rats underwent surgery without LCA ligation and served as a sham control group. LOX-1 expression was markedly increased during I/R ( P < 0.01 vs. sham control group). Simultaneously, the expression of matrix metalloproteinase-1 (MMP-1) and adhesion molecules (P-selectin, VCAM-1, and ICAM-1) was also increased in the I/R area ( P < 0.01 vs. sham control group). There was intense leukocyte accumulation in the I/R area in the saline-treated group. Treatment of rats with the LOX-1 antibody prevented I/R-induced upregulation of LOX-1 and reduced MMP-1 and adhesion molecule expression as well as leukocyte recruitment. LOX-1 antibody, but not nonspecific IgG, also reduced myocardial infarct size ( P < 0.01 vs. saline-treated I/R group). To explore the link between LOX-1 and adhesion molecule expression, we measured expression of oxidative stress-sensitive p38 mitogen-activated protein kinase (p38 MAPK). The activity of p38 MAPK was increased during I/R ( P < 0.01 vs. sham control), and use of LOX-1 antibody inhibited p38 MAPK activation ( P < 0.01). These findings indicate that myocardial I/R upregulates LOX-1 expression, which through p38 MAPK activation increases the expression of MMP-1 and adhesion molecules. Inhibition of LOX-1 exerts an important protective effect against myocardial I/R injury.

Regional myocardial ischemia-induced activation of MAPKs is associated with subcellular redistribution of caveolin and cholesterol

2006 ◽  
Vol 291 (2) ◽  
pp. H658-H667 ◽  
Author(s):  
Cherry Ballard-Croft ◽  
Adam C. Locklar ◽  
Gentian Kristo ◽  
Robert D. Lasley
Keyword(s):  
Myocardial Ischemia ◽  
P38 Mapk ◽  
Ischemia Reperfusion ◽  
Mapk Signaling ◽  
Mapk Activation ◽  
Caveolin 1 ◽  
Regional Myocardial Ischemia ◽  
Myocardial Ischemia Reperfusion ◽  
Heavy Fractions

Ischemia-reperfusion activates ERK and p38 MAPK in cardiac membranes, but the role of caveolae in MAPK signaling during this stress has not been studied. The purpose of this study was to determine the effect of in vivo myocardial ischemia-reperfusion on the level and distribution of caveolin-1 and -3 and cholesterol as well as MAPK activation in caveolin-enriched fractions. Adult male rats were subjected to in vivo regional myocardial ischemia induced by 25 min of coronary artery occlusion and 10 min ( n = 5) or 2 h ( n = 4) of reperfusion. Another group of rats served as appropriate nonischemic time controls ( n = 4). A discontinuous sucrose density gradient was used to isolate caveolae/lipid rafts from ischemic and nonischemic heart tissue. Caveolin-1 and -3, as well as cholesterol, were enriched in the light fractions. A redistribution of caveolin-3 and a reduction in caveolin-1 and cholesterol levels in the light fractions occurred after 10 min of reperfusion. The ERKs were activated in ischemic zone light and heavy fractions by 10 min of reperfusion. p44 ERK was activated after 2 h of reperfusion only in the light fractions, whereas p42 ERK phosphorylation was increased in the light and heavy fractions. Although no p38 MAPK activation occurred after 10 min of reperfusion, 2 h of reperfusion caused significant activation of p38 MAPK in nonischemic zone light and heavy fractions. These results show the importance of caveolar membrane/lipid rafts in MAPK signaling and suggest that subcellular compartmentation of p44/p42 ERKs and p38 MAPK may play distinct roles in the response to myocardial ischemia-reperfusion.

scholarly journals p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice

2005 ◽  
Vol 289 (1) ◽  
pp. F166-F174 ◽  
Author(s):  
Ganesan Ramesh ◽  
W. Brian Reeves
Keyword(s):  
Renal Dysfunction ◽  
P38 Mapk ◽  
Renal Injury ◽  
Acute Renal Injury ◽  
Mapk Activation ◽  
Mapk Activity ◽  
Tnf Α

Cisplatin is an important chemotherapeutic agent but can cause acute renal injury. Part of this acute renal injury is mediated through tumor necrosis factor-α (TNF-α). The pathway through which cisplatin mediates the production of TNF-α and injury is not known. Cisplatin activates p38 MAPK and induces apoptosis in cancer cells. p38 MAPK activation leads to increased production of TNF-α in ischemic injury and in macrophages. However, little is known concerning the role of p38 MAPK in cisplatin-induced renal injury. Therefore, we examined the effect of cisplatin on p38 MAPK activity and the role of p38 MAPK in mediating cisplatin-induced TNF-α production and renal injury. In vitro, cisplatin caused a dose-dependent activation of p38 MAPK in proximal tubule cells. Inhibition of p38 MAPK activation led to inhibition of TNF-α production. In vivo, mice treated with a single dose of cisplatin (20 mg/kg body wt) developed severe renal dysfunction at 72 h [blood urea nitrogen (BUN): 154 ± 34 mg/dl, creatinine: 1.4 ± 0.4 mg/dl], which was accompanied by an increase in kidney p38 MAPK activity and an increase in infiltrating leukocytes. However, animals treated with the p38 MAPK inhibitor SKF-86002 along with cisplatin showed less renal dysfunction (BUN: 55 ± 14 mg/dl, creatinine: 0.3 ± 0.02 mg/dl, P < 0.05), less severe histological damage, and fewer leukocytes compared with cisplatin+vehicle-treated animals. Serum levels of TNF-α, sTNFRI, and sTNFRII also increased significantly in cisplatin-treated mice compared with SKF-86002-treated mice ( P < 0.05). Kidney mRNA levels of TNF-α were significantly increased in cisplatin-treated mice compared with either SKF-86002- or saline-treated animals. The hydroxyl radical scavenger DMTU (100 mg·kg body wt−1·day−1) prevented the activation of p38 MAPK by cisplatin both in vitro and in vivo. DMTU also completely prevented cisplatin-induced renal injury (BUN: 140 ± 27 vs. 22 ± 2 mg/dl, P < 0.005) and the increase in serum TNF-α (33 ± 7 vs. 4 ± 2 pg/ml, P < 0.005) and kidney TNF-α mRNA in vivo. We conclude that hydroxyl radicals, either directly or indirectly, activate p38 MAPK and that p38 MAPK plays an important role in mediating cisplatin-induced acute renal injury and inflammation, perhaps through production of TNF-α.

Role of p38 MAPK in ischemia/reperfusion-induced gastric injury in mice

2010 ◽  
Vol 30 (3) ◽  
pp. 250-253
Author(s):  
Jian-ming WNAG ◽  
De-yi ZHENG ◽  
Yi-tao JIA ◽  
Jin-feng FU ◽  
Xing-feng ZHENG ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Ischemia Reperfusion ◽  
Gastric Injury

scholarly journals CircHIPK3 regulates the autophagy and apoptosis of hypoxia/reoxygenation-stimulated cardiomyocytes via the miR-20b-5p/ATG7 axis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Zhimei Qiu ◽  
Yan Wang ◽  
Weiwei Liu ◽  
Chaofu Li ◽  
Ranzun Zhao ◽  
...  
Keyword(s):  
Cell Injury ◽  
Ischemia Reperfusion ◽  
Circular Rna ◽  
Control Group ◽  
Loss Of Function ◽  
Cardiomyocyte Autophagy ◽  
Myocardial Ischemia Reperfusion ◽  
Injury Research ◽  
Hypoxia Reoxygenation

AbstractAutophagy and apoptosis are involved in myocardial ischemia/reperfusion (I/R) injury. Research indicates that circular RNA HIPK3 (circHIPK3) is crucial to cell autophagy and apoptosis in various cancer types. However, the role of circHIPK3 in the regulation of cardiomyocyte autophagy and apoptosis during I/R remains unknown. Our study aimed to examine the regulatory effect of circHIPK3 during myocardial I/R and investigate its mechanism in cardiomyocyte autophagy and apoptosis. Methods and results. The expression of circHIPK3 was upregulated during myocardial I/R injury and hypoxia/reoxygenation (H/R) injury of cardiomyocytes. To study the potential role of circHIPK3 in myocardial H/R injury, we performed gain-of-function and loss-of-function analyses of circHIPK3 in cardiomyocytes. Overexpression of circHIPK3 significantly promoted H/R-induced cardiomyocyte autophagy and cell injury (increased intracellular reactive oxygen species (ROS) and apoptosis) compared to those in the control group, while silencing of circHIPK3 showed the opposite effect. Further research found that circHIPK3 acted as an endogenous miR-20b-5p sponge to sequester and inhibit miR-20b-5p activity, resulting in increased ATG7 expression. In addition, miR-20b-5p inhibitors reversed the decrease in ATG7 induced by silencing circHIPK3. Conclusions. CircHIPK3 can accelerate cardiomyocyte autophagy and apoptosis during myocardial I/R injury through the miR-20b-5p/ATG7 axis. These data suggest that circHIPK3 may serve as a potential therapeutic target for I/R.

scholarly journals Structural basis for a complex I mutation that blocks pathological ROS production

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhan Yin ◽  
Nils Burger ◽  
Duvaraka Kula-Alwar ◽  
Dunja Aksentijević ◽  
Hannah R. Bridges ◽  
...  
Keyword(s):  
Point Mutation ◽  
Complex I ◽  
Structural Changes ◽  
Ischemia Reperfusion ◽  
Single Point ◽  
Structural Basis ◽  
Single Point Mutation ◽  
Ros Production

AbstractMitochondrial complex I is central to the pathological reactive oxygen species (ROS) production that underlies cardiac ischemia–reperfusion (IR) injury. ND6-P25L mice are homoplasmic for a disease-causing mtDNA point mutation encoding the P25L substitution in the ND6 subunit of complex I. The cryo-EM structure of ND6-P25L complex I revealed subtle structural changes that facilitate rapid conversion to the “deactive” state, usually formed only after prolonged inactivity. Despite its tendency to adopt the “deactive” state, the mutant complex is fully active for NADH oxidation, but cannot generate ROS by reverse electron transfer (RET). ND6-P25L mitochondria function normally, except for their lack of RET ROS production, and ND6-P25L mice are protected against cardiac IR injury in vivo. Thus, this single point mutation in complex I, which does not affect oxidative phosphorylation but renders the complex unable to catalyse RET, demonstrates the pathological role of ROS production by RET during IR injury.

Stimulation of pro-α1(I) collagen by TGF-β1 in mesangial cells: role of the p38 MAPK pathway

2001 ◽  
Vol 280 (3) ◽  
pp. F495-F504 ◽  
Author(s):  
Beek Yoke Chin ◽  
Amir Mohsenin ◽  
Su Xia Li ◽  
Augustine M. K. Choi ◽  
Mary E. Choi
Keyword(s):  
P38 Mapk ◽  
Intracellular Signaling ◽  
Mesangial Cells ◽  
Mapk Pathway ◽  
Dominant Negative ◽  
Glomerular Mesangial Cells ◽  
Mapk Activation ◽  
Mapk Phosphorylation ◽  
Collagen Mrna

Transforming growth factor-β1(TGF-β1) is a potent inducer of extracellular matrix protein synthesis and a key mediator of renal fibrosis. However, the intracellular signaling mechanisms by which TGF-β1stimulates this process remain incompletely understood. In this report, we examined the role of a major stress-activated intracellular signaling cascade, belonging to the mitogen-activated protein kinase (MAPK) superfamily, in mediating TGF-β1 responses in rat glomerular mesangial cells, using dominant-negative inhibition of TGF-β1 signaling receptors. We first stably transfected rat glomerular mesangial cells with a kinase-deleted mutant TGF-β type II receptor (TβR-IIM) designed to inhibit TGF-β1 signaling in a dominant-negative fashion. Next, expression of TβR-IIM mRNA was confirmed by Northern analysis. Cell surface expression and ligand binding of TβR-IIM protein were demonstrated by affinity cross-linking with 125I-labeled-TGF-β1. TGF-β1 rapidly induced p38 MAPK phosphorylation in wild-type and empty vector (pcDNA3)-transfected control mesangial cells. Interestingly, transfection with dominant-negative TβR-IIM failed to block TGF-β1-induced p38 MAPK phosphorylation. Moreover, dominant-negative TβR-IIMfailed to block TGF-β1-stimulated pro-α1(I) collagen mRNA expression and cellular protein synthesis, whereas TGF-β1-induced extracellular signal-regulated kinase (ERK) 1/ERK2 activation and antiproliferative responses were blocked by TβR-IIM. In the presence of a specific inhibitor of p38 MAPK, SB-203580, TGF-β1 was unable to stimulate pro-α1(I) collagen mRNA expression in the control and TβR-IIM-transfected mesangial cells. Finally, we confirmed that both p38 MAPK activation and pro-α1(I) collagen stimulation were TGF-β1 effects that were abrogated by dominant-negative inhibition of TGF-β type I receptor. Thus we show first demonstration of p38 MAPK activation by TGF-β1 in mesangial cells, and, given the rapid kinetics, this TGF-β1 effect is likely a direct one. Furthermore, our findings suggest that the p38 MAPK pathway functions as a component in the signaling of pro-α1(I) collagen induction by TGF-β1 in mesangial cells.

Exercise training improves myocardial tolerance to in vivo ischemia-reperfusion in the rat

1998 ◽  
Vol 275 (5) ◽  
pp. R1468-R1477 ◽  
Author(s):  
Scott K. Powers ◽  
Haydar A. Demirel ◽  
Heather K. Vincent ◽  
Jeff S. Coombes ◽  
Hisashi Naito ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Exercise Training ◽  
Endurance Exercise ◽  
Ischemia Reperfusion ◽  
Experimental Studies ◽  
Control Group ◽  
Sprague Dawley ◽  
Endurance Exercise Training ◽  
Nonprotein Thiols

Experimental studies examining the effects of regular exercise on cardiac responses to ischemia and reperfusion (I/R) are limited. Therefore, these experiments examined the effects of endurance exercise training on myocardial biochemical and physiological responses during in vivo I/R. Female Sprague-Dawley rats (4 mo old) were randomly assigned to either a sedentary control group or to an exercise training group. After a 10-wk endurance exercise training program, animals were anesthetized and mechanically ventilated, and the chest was opened by thoracotomy. Coronary occlusion was achieved by a ligature around the left coronary artery; occlusion was maintained for 20 min, followed by a 10-min period of reperfusion. Compared with untrained, exercise-trained animals maintained higher ( P < 0.05) peak systolic blood pressure throughout I/R. Training resulted in a significant ( P < 0.05) increase in ventricular nonprotein thiols, heat shock protein (HSP) 72, and the activities of superoxide dismutase (SOD), phosphofructokinase (PFK), and lactate dehydrogenase. Furthermore, compared with untrained controls, left ventricles from trained animals exhibited lower levels ( P < 0.05) of lipid peroxidation after I/R. These data demonstrate that endurance exercise training improves myocardial contractile performance and reduces lipid peroxidation during I/R in the rat in vivo. It appears likely that the improvement in the myocardial responses to I/R was related to training-induced increases in nonprotein thiols, HSP72, and the activities of SOD and PFK in the myocardium.

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