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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: CLINICAL-TRIAL ; MARKERS ; C-REACTIVE PROTEIN ; NATIONAL-HEALTH ; CARDIOVASCULAR-DISEASE ; PHYSICAL-ACTIVITY ; METAANALYSIS ; NUTRITION EXAMINATION SURVEY ; ENDOMETRIAL CANCER-RISK ; LIFE-STYLE INTERVENTION
    Abstract: Obese and sedentary persons have increased risk for cancer; inflammation is a hypothesized mechanism. We examined the effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in 439 women. Overweight and obese postmenopausal women were randomized to 1-year: caloric restriction diet (goal of 10% weight loss, N = 118), aerobic exercise (225 min/wk of moderate-to-vigorous activity, N = 117), combined diet + exercise (N = 117), or control (N = 87). Baseline and 1-year high-sensitivity C-reactive protein (hs-CRP), serum amyloid A (SAA), interleukin-6 (IL-6), leukocyte, and neutrophil levels were measured by investigators blind to group. Inflammatory biomarker changes were compared using generalized estimating equations. Models were adjusted for baseline body mass index (BMI), race/ethnicity, and age. Four hundred and thirty-eight (N = 1 in diet + exercise group was excluded) were analyzed. Relative to controls, hs-CRP decreased by geometric mean (95% confidence interval, P value): 0.92 mg/L (0.53-1.31, P 〈 0.001) in the diet and 0.87 mg/L (0.51-1.23, P 〈 0.0001) in the diet + exercise groups. IL-6 decreased by 0.34 pg/mL (0.13-0.55, P = 0.001) in the diet and 0.32 pg/mL (0.15-0.49, P 〈 0.001) in the diet + exercise groups. Neutrophil counts decreased by 0.31 x 10(9)/L (0.09-0.54, P = 0.006) in the diet and 0.30 x 10(9)/L (0.09-0.50, P = 0.005) in the diet + exercise groups. Diet and diet + exercise participants with 5% or more weight loss reduced inflammatory biomarkers (hs-CRP, SAA, and IL-6) compared with controls. The diet and diet + exercise groups reduced hs-CRP in all subgroups of baseline BMI, waist circumference, CRP level, and fasting glucose. Our findings indicate that a caloric restriction weight loss diet with or without exercise reduces biomarkers of inflammation in postmenopausal women, with potential clinical significance for cancer risk reduction.
    Type of Publication: Journal article published
    PubMed ID: 22549948
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  • 3
    Keywords: CLINICAL-TRIAL ; RISK ; BREAST-CANCER ; OBESITY ; COLON-CANCER ; CARDIOVASCULAR-DISEASE ; INSULIN-RESISTANCE ; metabolic syndrome ; BODY-MASS INDEX ; adipokines
    Abstract: BackgroundExcess body weight and a sedentary lifestyle are associated with the development of several diseases, including cardiovascular disease, diabetes and cancer in women. One proposed mechanism linking obesity to chronic diseases is an alteration in adipose-derived adiponectin and leptin levels. We investigated the effects of 12-month reduced calorie, weight loss and exercise interventions on adiponectin and leptin concentrations. MethodsOverweight/obese postmenopausal women (n=439) were randomized as follows: (i) a reduced calorie, weight-loss diet (diet; N=118), (ii) moderate-to-vigorous intensity aerobic exercise (exercise; N=117), (iii) a combination of a reduced calorie, weight-loss diet and moderate-to-vigorous intensity aerobic exercise (diet+exercise; N=117), and (iv) control (N=87). The reduced calorie diet had a 10% weight-loss goal. The exercise intervention consisted of 45min of moderate-to-vigorous aerobic activity 5days per week. Adiponectin and leptin levels were measured at baseline and after 12months of intervention using a radioimmunoassay. ResultsAdiponectin increased by 9.5% in the diet group and 6.6% in the diet+exercise group (both P0.0001 vs. control). Compared with controls, leptin decreased with all interventions (diet+exercise, -40.1%, P〈0.0001; diet, -27.1%, P〈0.0001; exercise, -12.7%, P=0.005). The results were not influenced by the baseline body mass index (BMI). The degree of weight loss was inversely associated with concentrations of adiponectin (diet, P-trend=0.0002; diet+exercise, P-trend=0.0005) and directly associated with leptin (diet, P-trend〈0.0001; diet+exercise, P-trend〈0.0001). ConclusionWeight loss through diet or diet+exercise increased adiponectin concentrations. Leptin concentrations decreased in all of the intervention groups, but the greatest reduction occurred with diet+exercise. Weight loss and exercise exerted some beneficial effects on chronic diseases via effects on adiponectin and leptin.
    Type of Publication: Journal article published
    PubMed ID: 23432360
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