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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS German Medical Science; VOL: 8; DOC20 /20100908/
    Publication Date: 2010-09-09
    Description: Objective: Ischemic heart disease is the leading cause of death worldwide. The complement system plays a major role in inflammation and tissue injury following myocardial ischemia and reperfusion (MI/R) injury. Systemic C5 inhibition in clinical studies has resulted in mixed results and the role of earlier complement components (e.g., C3a), upstream from C5 cleavage, has not been elucidated for MI/R injury. Therefore, we evaluated the role of C5 or C3a in a mouse model of MI/R injury.Methods: We performed experimental MI/R with 30 min of ischemia and 4 hr of reperfusion in 8-12 wk old C57BL/6 (WT) mice. Systemic C5 or C3a inhibition was performed with an anti-C5 monoclonal antibody (BB5.1) 30 min prior to reperfusion or with a C3a receptor antagonist (C3aRA). Since the C3aRA induces neutropenia that resolves within 120 min, we administered C3aRA at two different time points in two separate groups: 30 min prior to reperfusion within the neutropenic time frame and 120 min prior to reperfusion, when the neutropenia had resolved, but C3aRA remained active. Following MI/R, cardiac function was assessed via echocardiography, serum troponin I concentrations were measured as an index of myocardial cell death and myocardial inflammation was determined via myocardial polymorphonuclear leukocyte (PMN) infiltration.Results: In wild type mice, MI/R significantly decrease myocardial ejection fraction and increased serum troponin I levels and myocardial PMN infiltration compared to sham-operated animals. Systemic C5 inhibition, 30 min prior to reperfusion, significantly protected mice from MI/R injury, confirming an important role for C5 in murine MI/R injury.Treatment with the C3aRA, 30 min prior to reperfusion (i.e., within the neutropenic time frame), protected mice significantly from MI/R related injury. In contrast, administration of the C3aRA 120 min prior to reperfusion, when the neutropenia had resolved, but C3aRA remained active, did not prevent MI/R injury.Conclusions: These results confirm an important role for C5 cleavage in murine MI/R injury. At the same time, they suggest a minimal role for C3a, since neutropenia rather than C3a receptor antagonism appears to be responsible for C3aRA related amelioration in MI/R injury. While C5 inhibition in the clinical setting of MI/R does not appear to be therapeutic, our results raise the possibility that inhibition of either C5a or C5b-9 may be more advantageous than inhibition of C3a or complete inhibition of C5 in humans.
    Description: Einleitung: Die koronare Herzerkrankung ist weltweit die führende Todesursache. Das Komplementsystem spielt eine wichtige Rolle bei der Entzündungsreaktion und dem Gewebeschaden nach myokardialer Ischämie und Reperfusion (MI/R). Die Inhibition des Komplementfaktors C5 hatte in klinischen Studien unterschiedliche Ergebnisse gezeigt, und die Rolle von Komplementfaktoren, die oberhalb der C5-Spaltung in der Komplementkaskade liegen (z.B. C3a), wurde für MI/R nicht erforscht. Daher untersuchten wir die Rolle von C5 und C3a in einem MI/R-Mausmodell.Methoden: Wir führten in 12 Wochen alten C57BL/6 (WT)-Mäusen experimentell MI/R mit 30 min Ischämie und 4 h Reperfusion durch. Systemische Inhibition der Komplementfaktoren C5 oder C3a wurde mittels eines anti-C5 monoklonalen Antikörpers (BB5.1) 30 min vor der Reperfusion oder mit einem C3a-Rezeptorantagonist (C3aRA) durchgeführt. Da der C3aRA eine Neutropenie induziert, die innerhalb von 〈TextGroup〉 120 min 〈/TextGroup〉 abgeklungen ist, verabreichten wir den C3aRA in zwei unterschiedlichen Versuchsgruppen zu zwei Zeitpunkten: 30 min vor der Reperfusion, innerhalb der Neutropenie, und 120 min vor der Reperfusion, wenn die Neutropenie abgeklungen war, aber der C3aRA noch aktiv war. Nach MI/R untersuchten wir die kardiale Funktion mittels Echokardiographie, bestimmten die Serumkonzentration von Troponin I als Zeichen myokardialen Zelluntergangs und die myokardiale Infiltration mit Polymorphonukleären Zellen (PMN) als Maß myokardialer Inflammation. Ergebnisse: WT-Mäuse hatten nach MI/R im Vergleich zu sham-operierten Mäusen signifikant reduzierte Ejektionsfraktionen, während Troponin I und die myokardiale PMN-Infiltration signifikant erhöht waren. Systemische C5-Inhibierung 30 min vor der Reperfusion schützte Mäuse signifikant vor MI/R-Schädigung und bestätigt damit eine wichtige Rolle von C5 in MI/R im Mausmodell. Eine Behandlung mit dem C3aRA 30 min vor der Reperfusion, während der neutropenischen Phase, schützte die Mäuse signifikant vor MI/R-Schädigung. Eine Verabreichung des C3aRA 120 min vor der Reperfusion, wenn die Neutropenie abgeklungen war, aber der C3aRA noch aktiv war, verhinderte allerdings keine MI/R-Schädigung.Fazit: Diese Ergebnisse bestätigen eine wichtige Rolle für C5 bei MI/R im Mausmodell. Die durch den C3aRA verursachte Neutropenie, und nicht der C3a-Rezeptorantagonismus, scheint für die Abschwächung des MI/R-Schadens verantwortlich zu sein. Damit scheint C3a bei MI/R im Mausmodell nur eine untergeordnete Rolle zu spielen. Da die Inhibition des Komplementfaktors C5 in klinischen Studien nicht erfolgreich war, sprechen unsere Ergebnisse dafür, dass die Inhibition von C5a oder C5b-9 in klinischen Studien erfolgversprechender sein könnte als die Inhibition von C3a oder eine komplette Inhibition von C5.
    Keywords: ischemia ; reperfusion ; I/R ; cardiac ; myocardial ; heart ; ischemic heart disease ; C5 ; C3a ; complement ; Ischämie ; Reperfusion ; I/R ; kardial ; myokardial ; Herz ; koronare Herzerkrankung ; C5 ; C3a ; Komplement ; ddc: 610
    Language: English
    Type: article
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  • 2
    Keywords: EXPRESSION ; RISK ; COMPLEXES ; AMPLIFICATION ; OVARIAN-CANCER ; MUTATIONS ; VARIANT ; GENOME-WIDE ASSOCIATION ; GENETIC-VARIATION ; CONFERS SUSCEPTIBILITY
    Abstract: A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) 〉/= 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 x 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (Ptrend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. Cancer Res; 74(20); 5808-18. (c)2014 AACR.
    Type of Publication: Journal article published
    PubMed ID: 25320178
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