Activated platelets contribute importantly to myocardial reperfusion injury

2006 ◽  
Vol 290 (2) ◽  
pp. H692-H699 ◽  
Author(s):  
Yaqin Xu ◽  
Yuqing Huo ◽  
Marie-Claire Toufektsian ◽  
Susan I. Ramos ◽  
Yongguang Ma ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Knockout Mice ◽  
Platelet Rich Plasma ◽  
Ischemia Reperfusion ◽  
Myocardial Reperfusion ◽  
Myocardial Reperfusion Injury ◽  
Wild Type ◽  
Platelet Poor Plasma ◽  
Activated Platelets

Platelets become activated during myocardial infarction (MI), but the direct contribution of activated platelets to myocardial reperfusion injury in vivo has yet to be reported. We tested the hypothesis that activated platelets contribute importantly to reperfusion injury during MI in mice. After 30 min of ischemia and 60 min of reperfusion, P-selectin knockout mice had a significantly smaller infarct size than that of wild-type mice ( P < 0.05). Platelets were detected by P-selectin antibody in the previously ischemic region of wild-type mice as early as 2 min postreperfusion after 45 min, but not 20 min, of ischemia. The appearance of neutrophils in the heart was delayed when compared with platelets. Flow cytometry showed that the number of activated platelets more than doubled after 45 min of ischemia when compared with 20 min of ischemia or sham treatment ( P < 0.05). Platelet-rich or platelet-poor plasma was then transfused from either sham-operated or infarcted mice after 45 and 10 min of ischemia-reperfusion to mice undergoing 20 and 60 min of ischemia-reperfusion. Infarct size was increased by threefold and platelet accumulation was remarkably enhanced in mice treated with wild-type, MI-activated platelet-rich plasma but not in mice receiving either platelet-poor plasma from wild types or MI-activated platelet-rich plasma from P-selectin knockout mice. In conclusion, circulating platelets become activated early during reperfusion and their activation depends on the duration of the preceding coronary occlusion and is proportional to the extent of myocardial injury. Activated platelets play an important role in the process of myocardial ischemia-reperfusion injury, and platelet-derived P-selectin is a critical mediator.

Myocardial reperfusion injury management: erythropoietin compared with postconditioning

2009 ◽  
Vol 297 (6) ◽  
pp. H2035-H2043 ◽  
Author(s):  
Sophie Tamareille ◽  
Nehmat Ghaboura ◽  
Frederic Treguer ◽  
Dalia Khachman ◽  
Anne Croué ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Isolated Heart ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Myocardial Reperfusion ◽  
Myocardial Reperfusion Injury ◽  
Gsk 3Β ◽  
Developed Pressure

Ischemic postconditioning (IPost) and erythropoietin (EPO) have been shown to attenuate myocardial reperfusion injury using similar signaling pathways. The aim of this study was to examine whether EPO is as effective as IPost in decreasing postischemic myocardial injury in both Langendorff-isolated-heart and in vivo ischemia-reperfusion rat models. Rat hearts were subjected to 25 min ischemia, followed by 30 min or 2 h of reperfusion in the isolated-heart study. Rats underwent 45 min ischemia, followed by 24 h of reperfusion in the in vivo study. In both studies, the control group ( n = 12; ischemia-reperfusion only) was compared with IPost ( n = 16; 3 cycles of 10 s reperfusion/10 s ischemia) and EPO ( n = 12; 1,000 IU/kg) at the onset of reperfusion. The following resulted. First, in the isolated hearts, IPost or EPO significantly improved postischemic recovery of left ventricular developed pressure. EPO induced better left ventricular developed pressure than IPost at 30 min of reperfusion (73.18 ± 10.23 vs. 48.11 ± 7.92 mmHg, P < 0.05). After 2 h of reperfusion, the infarct size was significantly lower in EPO-treated hearts compared with IPost and control hearts (14.36 ± 0.60%, 19.11 ± 0.84%, and 36.21 ± 4.20% of the left ventricle, respectively; P < 0.05). GSK-3β phosphorylation, at 30 min of reperfusion, was significantly higher with EPO compared with IPost hearts. Phosphatidylinositol 3-kinase and ERK1/2 inhibitors abolished both EPO- and IPost-mediated cardioprotection. Second, in vivo, IPost and EPO induced an infarct size reduction compared with control (40.5 ± 3.6% and 28.9 ± 3.1%, respectively, vs. 53.7 ± 4.3% of the area at risk; P < 0.05). Again, EPO decreased significantly more infarct size and transmurality than IPost ( P < 0.05). In conclusion, with the use of our protocols, EPO showed better protective effects than IPost against reperfusion injury through higher phosphorylation of GSK-3β.

Factors modifying protective effect of anti-CD18 antibodies on myocardial reperfusion injury in dogs

1996 ◽  
Vol 270 (1) ◽  
pp. H53-H64 ◽  
Author(s):  
R. G. Perez ◽  
M. Arai ◽  
C. Richardson ◽  
A. DiPaula ◽  
C. Siu ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Myocardial Reperfusion ◽  
Myocardial Reperfusion Injury ◽  
H2o2 Production ◽  
Myeloperoxidase Activity ◽  
Collateral Flow ◽  
Severe Ischemia

Anti-CD18 monoclonal antibodies (MAb) have demonstrated variable protection against neutrophil (PMN)-mediated myocardial reperfusion injury. To identify factors contributing to this variability, open-chest dogs underwent coronary artery occlusion for 90 min followed by reperfusion for 3.5 h. Ten minutes before reperfusion the dogs received saline (n = 18) or one of three anti-CD18 MAb: MHM.23, R15.7, or PLM-2 (2, 1, and 1 mg/kg and n = 19, 8, and 4, respectively). Collateral flow was measured with radioactive microspheres, area at risk was assessed with monastral blue dye, and infarct size was measured postmortem by triphenyltetrazolium chloride. In vitro, all three MAb bound to canine PMNs, but only MHM.23 and R15.7 inhibited their adherence to keyhole limpet hemocyanin-coated plastic. In vivo, only MHM.23 and R15.7 significantly reduced infarct size after adjusting for the effect of collateral flow. MHM.23 afforded protection in dogs with moderate ischemia (epicardial collateral flow > 0.1 ml.min-1.g-1, infarct size reduced 46%) but not in dogs with more severe ischemia. Only R15.7 was effective in dogs with severe ischemia. Although MHM.23 and R15.7 produced similar inhibition of tissue PMN accumulation, as reflected by myeloperoxidase activity. R15.7 markedly inhibited H2O2 production by PMNs after exposure to platelet-activating factor, whereas MHM.23 had only a minimal effect. The effectiveness of different anti-CD18 MAb in preventing reperfusion injury appears to be 1) highly dependent on the specific anti-CD18 MAb employed, 2) predicted only partially by in vitro binding to PMNs, static in vitro tests of PMN adherence, or the extent of inhibition of PMN accumulation in vivo, 3) related more to their ability to inhibit oxidant release from activated PMNs, and 4) strongly influenced by the severity of myocardial ischemia before reperfusion.

Cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2 is mediated by the MAPK cascade

2005 ◽  
Vol 289 (5) ◽  
pp. H2167-H2175 ◽  
Author(s):  
Stacey L. House ◽  
Kevin Branch ◽  
Gilbert Newman ◽  
Thomas Doetschman ◽  
Jo El J. Schultz
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Mapk Signaling ◽  
Low Flow ◽  
Wild Type ◽  
Erk Inhibition ◽  
Sb 203580

Our laboratory showed previously that cardiac-specific overexpression of FGF-2 [FGF-2 transgenic (Tg)] results in increased recovery of contractile function and decreased infarct size after ischemia-reperfusion injury. MAPK signaling is downstream of FGF-2 and has been implicated in other models of cardioprotection. Treatment of FGF-2 Tg and wild-type hearts with U-0126, a MEK-ERK pathway inhibitor, significantly reduced recovery of contractile function after global low-flow ischemia-reperfusion injury in FGF-2 Tg (86 ± 2% vehicle vs. 66 ± 4% U-0126; P < 0.05) but not wild-type (61 ± 7% vehicle vs. 67 ± 7% U-0126) hearts. Similarly, MEK-ERK inhibition significantly increased myocardial infarct size in FGF-2 Tg (12 ± 3% vehicle vs. 31 ± 2% U-0126; P < 0.05) but not wild-type (30 ± 4% vehicle vs. 36 ± 7% U-0126) hearts. In contrast, treatment of FGF-2 Tg and wild-type hearts with SB-203580, a p38 inhibitor, did not abrogate FGF-2-induced cardioprotection from postischemic contractile dysfunction. Instead, inhibition of p38 resulted in decreased infarct size in wild-type hearts (30 ± 4% vehicle vs. 11 ± 2% SB-203580; P < 0.05) but did not alter infarct size in FGF-2 Tg hearts (12 ± 3% vehicle vs. 14 ± 1% SB-203580). Western blot analysis of ERK and p38 activation revealed signaling alterations in FGF-2 Tg and wild-type hearts during early ischemia or reperfusion injury. In addition, MEK-independent ERK inhibition by p38 was observed during early ischemic injury. Together these data suggest that activation of ERK and inhibition of p38 by FGF-2 is cardioprotective during ischemia-reperfusion injury.

scholarly journals Nanosecond pulsed platelet-rich plasma (nsPRP) improves mechanical and electrical cardiac function following myocardial reperfusion injury

2016 ◽  
Vol 4 (4) ◽  
pp. e12710 ◽  
Author(s):  
Barbara Hargrave ◽  
Frency Varghese ◽  
Nektarios Barabutis ◽  
John Catravas ◽  
Christian Zemlin
Keyword(s):  
Cardiac Function ◽  
Reperfusion Injury ◽  
Platelet Rich Plasma ◽  
Myocardial Reperfusion ◽  
Myocardial Reperfusion Injury

scholarly journals Role of Caveolin-3 and Glucose Transporter-4 in Isoflurane-induced Delayed Cardiac Protection

2010 ◽  
Vol 112 (5) ◽  
pp. 1136-1145 ◽  
Author(s):  
Yasuo M. Tsutsumi ◽  
Yoshitaka Kawaraguchi ◽  
Yousuke T. Horikawa ◽  
Ingrid R. Niesman ◽  
Michael W. Kidd ◽  
...  
Keyword(s):  
Infarct Size ◽  
Knockout Mice ◽  
Glucose Transporter ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Transporter 4 ◽  
Wild Type ◽  
Cardiac Protection ◽  
Caveolin 1 ◽  
Discontinuous Sucrose Gradient

Background Caveolae are small, flask-like invaginations of the plasma membrane. Caveolins are structural proteins found in caveolae that have scaffolding properties to allow organization of signaling. The authors tested the hypothesis that delayed cardiac protection induced by volatile anesthetics is caveolae or caveolin dependent. Methods An in vivo mouse model of ischemia-reperfusion injury with delayed anesthetic preconditioning (APC) was tested in wild-type, caveolin-1 knockout, and caveolin-3 knockout mice. Mice were exposed to 30 min of oxygen or isoflurane and allowed to recover for 24 h. After 24 h recovery, mice underwent 30-min coronary artery occlusion followed by 2 h of reperfusion at which time infarct size was determined. Biochemical assays were also performed in excised hearts. Results Infarct size as a percent of the area at risk was reduced by isoflurane in wild-type (24.0 +/- 8.8% vs. 45.1 +/- 10.1%) and caveolin-1 knockout mice (27.2 +/- 12.5%). Caveolin-3 knockout mice did not show delayed APC (41.5 +/- 5.0%). Microscopically distinct caveolae were observed in wild-type and caveolin-1 knockout mice but not in caveolin-3 knockout mice. Delayed APC increased the amount of caveolin-3 protein but not caveolin-1 protein in discontinuous sucrose-gradient buoyant fractions. In addition, glucose transporter-4 was increased in buoyant fractions, and caveolin-3/glucose transporter-4 colocalization was observed in wild-type and caveolin-1 knockout mice after APC. Conclusions These results show that delayed APC involves translocation of caveolin-3 and glucose transporter-4 to caveolae, resulting in delayed protection in the myocardium.

A sialyl Lewis(x)-containing carbohydrate reduces infarct size: role of selectins in myocardial reperfusion injury

1996 ◽  
Vol 271 (5) ◽  
pp. H2086-H2096 ◽  
Author(s):  
D. M. Flynn ◽  
A. J. Buda ◽  
P. R. Jeffords ◽  
D. J. Lefer
Keyword(s):  
Blood Flow ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Left Ventricular ◽  
Myocardial Reperfusion ◽  
Myocardial Reperfusion Injury ◽  
Sialyl Lewis X ◽  
Control Group ◽  
Leukocyte Accumulation ◽  
Sialyl Lewis

Previous studies have implicated the selectins (P- and L-selectin) in the acute phase of myocardial reperfusion injury. However, it is unclear whether these adhesion molecules are involved in the pathogenesis of myocardial reperfusion associated with longer periods of reperfusion. Dogs (n = 8/group) were subjected to 90 min of coronary ischemia and 48 h of reperfusion. Animals were initially treated with a 35 mg/kg intravenous bolus of a sialyl Lewis(x) oligosaccharide (SLe(x)-OS) 10 min before reperfusion, followed by a 1.75 mg.kg-1.h-1 infusion for the first 24 h of reperfusion. A control group of dogs received a normal saline bolus followed by saline infusion for the first 24 h of reperfusion. In a subsequent group of dogs treatment consisted of only the 35 mg/kg bolus of SLe(x)-OS to help elucidate the time course of selectin involvement. The saline control group exhibited marked decreases in blood flow in the ischemic-reperfused myocardium, sustained depression of left ventricular function, an average infarct size of 29 +/- 5% of the myocardial area at risk, and excessive polymorphonuclear leukocyte accumulation in the infarcted myocardium after 48 h of reperfusion. Dogs that received a bolus followed by an infusion of SLe(x)-OS exhibited significant preservation of myocardial blood flow and left ventricular function at 4.5 and 48 h of reperfusion, dramatic attenuation (56%) of infarct size (P < 0.05), and a 55% reduction (P < 0.05) in polymorphonuclear leukocyte accumulation compared with the saline group. Interestingly, SLe(x)-OS bolus treatment alone exerted early (i.e., at 4.5 h) cardioprotective effects that waned by 48 h of reperfusion. These results demonstrate that the selectin family of adhesion molecules plays an extended role in myocardial reperfusion injury and is not only involved in the acute phase of this disease process.

scholarly journals Hypothermia for Reduction of Myocardial Reperfusion Injury in Acute Myocardial Infarction: Closing the Translational Gap

2021 ◽  
Author(s):  
Mohamed El Farissi ◽  
Danielle C.J. Keulards ◽  
Jo M. Zelis ◽  
Marcel van ’t Veer ◽  
Frederik M. Zimmermann ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Myocardial Reperfusion ◽  
Myocardial Reperfusion Injury ◽  
Current Status ◽  
Myocardial Salvage ◽  
Nonlinear Phenomena ◽  
Comprehensive Overview

Myocardial reperfusion injury—triggered by an inevitable inflammatory response after reperfusion—may undo a considerable part of the myocardial salvage achieved through timely percutaneous coronary intervention in patients with acute myocardial infarction. Because infarct size is strongly correlated to mortality and risk of heart failure, the importance of endeavors for cardioprotective therapies to attenuate myocardial reperfusion injury and decrease infarct size remains undisputed. Myocardial reperfusion injury is the result of several complex nonlinear phenomena, and for a therapy to be effective, it should act on multiple targets involved in this injury. In this regard, hypothermia remains a promising treatment despite a number of negative randomized controlled trials in humans with acute myocardial infarction so far. To turn the tide for hypothermia in patients with acute myocardial infarction, sophisticated solutions for important limitations of systemic hypothermia should continue to be developed. In this review, we provide a comprehensive overview of the pathophysiology and clinical expression of myocardial reperfusion injury and discuss the current status and possible future of hypothermia for cardioprotection in patients with acute myocardial infarction.

Abstract 1616: The Role For Caveolin And Caveolae In Delayed Protection From Ischemia-reperfusion Injury

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Yasuo M Tsutsumi ◽  
Yoshihiro Ishikawa ◽  
David M Roth ◽  
Hemal H Patel
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Volatile Anesthetics ◽  
Wild Type ◽  
Cardiac Protection ◽  
Glut 4 ◽  
Discontinuous Sucrose Gradient ◽  
The Impact

Introduction: Caveolae are small, flask-like invaginations of the plasma membrane. Caveolins are structural proteins found in caveolae that have scaffolding properties to allow organization of signaling. We have recently shown that both caveolin-1 and caveolin-3 knockout (Cav-1 KO and Cav-3 KO, respectively) mice are unable to be protected from myocardial ischemia-reperfusion injury by acute treatment with volatile anesthetics. Therefore, we tested the hypothesis that delayed cardiac protection induced by volatile anesthetics is caveolin-dependent. Methods: Biochemical assays were performed in excised hearts. Electron microscopy was used to assess caveolae formation. An in vivo mouse model of ischemia-reperfusion injury with delayed anesthetic preconditioning (delayed APC) was tested in wild-type (WT), Cav-1 KO, and Cav-3 KO mice. Mice were exposed to 30 min isoflurane or oxygen and allowed to recover for 24 h. After 24 h recovery, mice underwent 30 min left anterior descending coronary artery occlusion, followed by 2 h of reperfusion at which time infarct size was determined. Results: To elucidate a role for caveolins in delayed APC, wild-type mice were exposed to delayed APC and hearts were fractionated on a discontinuous sucrose gradient to isolate buoyant caveolar membranes. Delayed APC increased the amount of Cav-3 protein but not Cav-1 protein in buoyant fractions. Glucose transporter-4 (GLUT-4), known to interact with Cav-3 and affect cardiac protection, was also increased in buoyant fractions after APC. Microscopically distinct caveolae were observed in WT and Cav-1 KO mice but not Cav-3 KO mice. We assessed the impact of caveolae formation in induction of delayed APC. Infarct size as a percent of the area at risk was reduced by isoflurane in WT (24.0 ± 2.5% vs. 45.1 ± 2.9%, p < 0.05) and Cav-1 KO mice (27.2 ± 4.4%). Cav-3 KO mice did not show delayed APC (41.5 ± 2.2%). Conclusions: These results demonstrate that isoflurane-induced delayed preconditioning involves translocation of Cav-3 and GLUT-4 to caveolae and the presence of microscopically distinct caveolae (dependent on Cav-3 expression) are a requisite for induction of delayed protection in the myocardium. This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).

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