A Novel Strategy for Myocardial Protection by Combined Antibody Therapy Inhibiting Both P-Selectin and Intercellular Adhesion Molecule-1 Via Retrograde Intracoronary Route

Fukushima, Satsuki; Coppen, Steven R.; Varela-Carver, Anabel; Yamahara, Kenichi; Sarathchandra, Padmini; Smolenski, Ryszard T.; Yacoub, Magdi H.; Suzuki, Ken

doi:10.1161/circulationaha.105.000794

Cited by 41 publications

(32 citation statements)

References 21 publications

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“…Fukushima et al 19 have reported previously that inhibition of ICAM-1 and/or P-selectin using antibody therapy immediately before reperfusion in a rat model of myocardial I/R injury was successful in attenuating infarct size and reducing the accumulation of leukocytes in the ischemic area. Thus, our finding that Egfl7 limits HCAEC expression of ICAM-1 after H/R injury leads us to hypothesize that it may also be protective against myocardial I/R injury in keeping with the findings of Fukushima et al 19 …”

Section: Effect Of Egfl7 On Icam-1 Productionmentioning

confidence: 99%

Epidermal Growth Factor-Like Domain 7 Suppresses Intercellular Adhesion Molecule 1 Expression in Response to Hypoxia/Reoxygenation Injury in Human Coronary Artery Endothelial Cells

et al. 2010

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Background-Epidermal growth factor-like domain 7 (Egfl7) is a chemoattractant for endothelial cells, and its expression is restricted to endothelial cells. Hypoxia/reoxygenation (H/R) induced endothelial injury that occurs during transplantation contributes to the subsequent development of allograft vasculopathy. We investigated the effect of Egfl7 on endothelial cell intercellular adhesion molecule 1 expression in response to H/R injury. Methods and Results-Human coronary artery endothelial cells were submitted to hypoxia (0.1% O 2 ) followed by normoxia (21% O 2 ) in the presence or absence of Egfl7 (100 ng/mL). Hypoxia alone increased the expression of Egfl7ϫ140Ϯ8% of control at 3 hours (nϭ6; PϽ0.05) and 385Ϯ50% of control at 6 hours (nϭ6; PϽ0.001). Incubation with Egfl7 during the reoxygenation period prevented intercellular adhesion molecule 1 upregulation (mean fluorescence intensity: 5.37Ϯ0.92 versus 3.81Ϯ0.21; PϽ0.05; nϭ4 per group). Nuclear factor-B nuclear localization on H/R injury was blocked by Egfl7 administration (cytosolic/nuclear ratio of 0.93Ϯ0.01 versus 1.44Ϯ0.24; PϽ0.05; nϭ4 per group). Inhibitor of nuclear factor-B protein level was significantly reduced on H/R injury (26Ϯ4.6% of control expression; PϽ0.05; nϭ4 per group); however, concurrent incubation with Egfl7 attenuated this reduction (46Ϯ6.2% of control expression; PϽ0.05 when compared with H/R injury alone; nϭ4 per group). Conclusions-Our study reveals the novel observation that hypoxia upregulates human coronary artery endothelial cells expression of Egfl7 and that Egfl7 inhibits expression of intercellular adhesion molecule 1 subsequent to H/R injury. Mechanistically, Egfl7 prevented nuclear factor-B nuclear localization and augmented inhibitor of nuclear factor-B protein levels, suggesting that it inhibits nuclear factor-B activation, a key step in the inflammatory activation of endothelial cells. Egfl7 may be protective against H/R injury incurred during transplantation and may modulate the events that lead to the development of graft vasculopathy. (Circulation. 2010;122[suppl 1]:S156 -S161.)

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Section: Effect Of Egfl7 On Icam-1 Productionmentioning

confidence: 99%

Epidermal Growth Factor-Like Domain 7 Suppresses Intercellular Adhesion Molecule 1 Expression in Response to Hypoxia/Reoxygenation Injury in Human Coronary Artery Endothelial Cells

et al. 2010

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“…P-selectin knock-out mice demonstrate a significantly smaller infarct size than that of wild-type mice after transient coronary occlusion [3]. Administration of antibodies against P-selectin reduces infarct size in animals [4]. However, to date, despite the large amount of experimental data, possible associations of platelet-bound P-selectin with the extent of myocardial damage in patients with ACS are poorly described.…”

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confidence: 99%

Platelet‐bound P‐selectin expression in patients with coronary artery disease: impact on clinical presentation and myocardial necrosis, and effect of diabetes mellitus and anti‐platelet medication

Stellos

Bigalke

Stakos

et al. 2010

Journal of Thrombosis and Haemostasis

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To cite this article: Stellos K, Bigalke B, Stakos D, Henkelmann N, Gawaz M. Platelet-bound P-selectin expression in patients with coronary artery disease: impact on clinical presentation and myocardial necrosis, and effect of diabetes mellitus and anti-platelet medication. J Thromb Haemost 2010; 8: 205-7.Increasing evidence suggests that platelet activation plays an important role in the pathogenesis and clinical presentation of acute coronary syndromes (ACS) both by mediating thrombotic occlusion of large epicardial coronary arteries and influencing the extent of myocardial injury [1]. Platelet-bound P-selectin appears to represent a critical mediator in all of these processes [2]. P-selectin knock-out mice demonstrate a significantly smaller infarct size than that of wild-type mice after transient coronary occlusion [3]. Administration of antibodies against P-selectin reduces infarct size in animals [4]. However, to date, despite the large amount of experimental data, possible associations of platelet-bound P-selectin with the extent of myocardial damage in patients with ACS are poorly described. Platelet-bound P-selectin has also been studied as a potential biomarker in ACS, but its association with clinical presentation has only been examined in a small number of studies [5][6][7].The goal of the present study was to assess possible associations between platelet P-selectin and extent of myocardial injury, measured by troponin I (Tn-I) and creatine kinase-MB (CK-MB), and to investigate the relationship between Pselectin expression and clinical presentation in patients with coronary artery disease (CAD).A total of 667 consecutive patients that were referred to our hospital for symptomatic CAD and that underwent coronary intervention were studied. All patients gave written informed consent and the study was approved by the local institutional ethical committee. The patients were divided into two groups, those with stable angina (SAP; n = 348) and those with ACS (n = 319). The ACS group comprised patients with STsegment elevation myocardial infarction (STEMI; n = 86), patients with non-ST-segment elevation myocardial infarction (NSTEMI; n = 53) and those with unstable angina (UA) with normal CK-MB but minimal myocardial necrosis (Tn-I pos.UA; n = 180).Blood samples for flow cytometry (P-selectin) and myocardial necrosis markers were collected before coronary intervention and analyzed immediately, as previously described [8]. Peak values of Tn-I, CK, CK-MB were determined during the course of hospital stay. Specific monoclonal antibody binding was expressed as mean fluorescence intensity (MFI) and was used as a quantitative measurement of platelet P-selectin surface expression. The intra-and inter-assay of the coefficient of variation of P-selectin expression in healthy subjects were 4.2% and 15.4%, respectively.Platelet P-selectin expression was increased in patients with ACS compared with those with SAP with MFI ± 95%CI of 12.1 ± 0.6 and 10.43 ± 0.36, respectively (P = 0.002; Fig. 1A, B) independent of age, ge...

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“…Inhibiting P‐selectin–dependent functions such as platelet activation and leukocyte recruitment has initially emerged as a promising therapeutic approach in preventing neointimal formation 10, 19, 20, 21. Based on encouraging results from animal models of myocardial ischemia–reperfusion injury and phase I clinical studies,22, 23, 24, 25 the recent SELECT‐ACS trial has then extended the concept of targeting P‐selectin pathways to patients with acute coronary syndromes undergoing PCI and demonstrated the efficacy of the P‐selectin antagonist inclacumab in reducing periprocedural myocardial damage 14…”

Section: Discussionmentioning

confidence: 99%

Effects of the P‐Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention According to Timing of Infusion: Insights From the SELECT‐ACS Trial

Stähli

Gebhard

Duchatelle

et al. 2016

JAHA

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BackgroundThe Effects of the P‐Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention for Non‐ST‐Segment Elevation Myocardial Infarction (SELECT‐ACS) trial suggested beneficial effects of inclacumab, a monoclonal antibody directed against P‐selectin, on periprocedural myocardial damage. This study evaluated the effect of inclacumab on myocardial damage according to varying time intervals between study drug infusion and percutaneous coronary intervention (PCI).Methods and ResultsPatients (n=544) enrolled in the SELECT‐ACS trial and randomized to receive 1 infusion of placebo or inclacumab (5 or 20 mg/kg, administered between 1 and 24 hours before PCI) were divided according to the time interval between study drug infusion and PCI. The primary end point was the change in troponin I from baseline at 16 and 24 hours after PCI. In patients receiving inclacumab 20 mg/kg with a short (less than median) time interval between infusion and PCI, placebo‐adjusted geometric mean percent changes in troponin I, creatine kinase–myocardial band, and peak troponin I at 24 hours were −45.6% (P=0.005), −30.7% (P=0.01), and −37.3% (P=0.02), respectively. No significant changes were observed in patients with a long (greater than median) time interval between infusion and PCI. Placebo‐adjusted geometric mean percent changes in troponin I and creatine kinase–myocardial band were −43.5% (P=0.02) and −26.0% (P=0.07), respectively, when inclacumab 20 mg/kg was administered between 1 and 3 hours before PCI, whereas the drug had no effect with longer intervals.ConclusionsInclacumab 20 mg/kg significantly reduces myocardial damage after PCI in patients with non–ST‐segment elevation myocardial infarction, and benefits are larger when the infusion is administered <3 hours before PCI.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01327183.

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A Novel Strategy for Myocardial Protection by Combined Antibody Therapy Inhibiting Both P-Selectin and Intercellular Adhesion Molecule-1 Via Retrograde Intracoronary Route

Cited by 41 publications

References 21 publications

Epidermal Growth Factor-Like Domain 7 Suppresses Intercellular Adhesion Molecule 1 Expression in Response to Hypoxia/Reoxygenation Injury in Human Coronary Artery Endothelial Cells

Epidermal Growth Factor-Like Domain 7 Suppresses Intercellular Adhesion Molecule 1 Expression in Response to Hypoxia/Reoxygenation Injury in Human Coronary Artery Endothelial Cells

Platelet‐bound P‐selectin expression in patients with coronary artery disease: impact on clinical presentation and myocardial necrosis, and effect of diabetes mellitus and anti‐platelet medication

Effects of the P‐Selectin Antagonist Inclacumab on Myocardial Damage After Percutaneous Coronary Intervention According to Timing of Infusion: Insights From the SELECT‐ACS Trial

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