C-reactive protein (CRP) is made in liver and its serum concentration increases in inflammation. Measurement of serum CRP is recommended for use as an indicator of inflammation and predictor of atherosclerosis. Cholesterol-lowering drugs statins also lower CRP. To evaluate statin-mediated CRP reduction and to reassess clinical usefulness of CRP, we investigated regulation of CRP gene expression. Here, we show that pravastatin and simvastatin prevent the induction of CRP expression in human hepatoma Hep3B cells exposed to proinflammatory cytokines IL-6 and IL-1β. The nitric oxide (NO) donor, sodium nitroprusside, also prevented the induction of CRP expression while the CRP inducers IL-6 and IL-1β were present with the cells. The effect of NO on CRP expression was at the level of transcription. These findings suggest that the decrease in CRP level in vivo after statin-treatment does not necessarily reflect absence of inflammation, and that NO-releasing drugs have the potential to reduce serum CRP levels. Thus, the measurement of serum CRP levels alone in individuals on statin/NO-therapy is not as useful as was imagined.

C-reactive protein (CRP) that has been conserved throughout evolution is a host-defense molecule. Its attraction towards phosphocholine-ligands, such as modified low-density lipoprotein, and apoptotic cells leads to the "masking" of these substances that have the capabilities to otherwise engage in deleterious activities. Complement activation by CRP complexes and the modulation by CRP of complement activation by its ligands add up to its beneficial effects. In the presence of CRP, production of membrane-damaging last product of the complement pathway is arrested. CRP is currently serving as an indicator of cardiovascular diseases, but to pinpoint the role of CRP in atherosclerosis, a drug that can lower cholesterol levels, but not the CRP levels, is needed for experimentation.

Acute phase proteins (APP) are ideal biomarkers for inflammation due to their stability, relative ease of assay and apparent relation between their concentration and the extent of the insult to tissue. C-reactive protein (CRP) is a positive major APP in dogs and can be used as a predictive marker for risk of disease and to monitor the response to treatment. Increased concentrations in certain diseases are associated with poor outcome. This cross-sectional, observational study of 75 dogs naturally infected with Babesia rossi, a cause of virulent canine babesiosis, was designed to examine the association of CRP concentration at admission and the magnitude of CRP change 24 hours after admission with outcome. Dogs were excluded if there was evidence of concurrent inflammatory diseases at the time of admission, infection with subtypes other than B. rossi, concurrent Ehrlichia canis infections or euthanasia for reasons other than poor prognosis. Diagnosis was confirmed by polymerase chain reaction and reverse line blot. CRP concentrations were determined by an automated human CRP Turbidometric Immunoassay (TIA), previously validated for use in dogs (Bayer CRP TIA, Newbury, UK), on serum samples collected by jugular venipuncture on admission, prior to any therapy, and thereafter daily until discharge or death. There was no significant difference in admission CRP concentration between survivors (n = 57; median = 97.4 mg/l; mean ± SD = 107.5 ± 49.5), and non-survivors (n = 11; median = 101.4 mg/l; mean ± SD = 122.1 ± 64.6) (p = 0.39). After elimination of non-significant predictors, a multiple exact logistic regression model for predicting mortality contained glucose and CRP. Mortality was associated with decreased glucose levels (p = 0.0002) and increased CRP levels (p = 0.045) on admission. Multiple regression analysis failed to show a significant relationship between admission CRP concentration and number of days of hospitalization in the survivors, adjusting for age and sex (p = 0.65). No significance was found in the relationship between the magnitude of change in CRP concentration 24 hours after admission, and the number of days of hospitalization in survivors, (p = 0.34). Using an admission CRP concentration cut-off of 60 mg/l, survival proportions between the two groups were no different (p = 0.34) and when applied to the group of dogs that survived, it was not associated with length of hospitalization (p = 0.25). In corroboration with previous reports glucose was identified as a major prognostic marker for mortality, but additionally the pro-inflammatory marker CRP was identified as a significant co-prognosticator. Copyright / Dissertation (MMedVet)--University of Pretoria, 2009. / Companion Animal Clinical Studies / unrestricted

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13110号 / 論医博第2128号 / 新制||医||1022(附属図書館) / (主査)教授 髙折 晃史, 教授 佐藤 俊哉, 教授 川上 浩司 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

The purpose of the present study was to examine the cross-sectional relationship between physical activity and C-reactive protein (CRP) in 211 middle-aged women (43.1 + 3.0 years). A secondary objective was to determine the extent to which body fat percentage operated as a confounder in the association between physical activity and CRP. Physical activity was objectively measured using MTI accelerometers, which the subjects wore for seven continuous days. Fasting blood samples were taken, from which CRP was measured using a solid phase ELISA. Body fat percentage was assessed using the Bod Pod. Results showed that physical activity was significantly and inversely related to CRP concentrations (F = 4.20, p = 0.042). Specifically, regression analysis showed that for each 100,000 count increase in physical activity (about 25 minutes of moderate exercise), there was a decrease of 0.026 mg/L of CRP. However, after adjusting for differences in body fat percentage, measured physical activity was no longer a significant predictor of CRP (F = 0.01, p = 0.927). These findings suggest that although higher physical activity levels are related to lower CRP levels, this relationship is almost entirely a function of differences in body fat.

Objective- To investigate the extent to which changes in body fat percentage (BF%) and weight (BW) relate to changes in C-reactive protein (CRP) in women, while statistically controlling for possible confounders, such as age, initial body weight, and menopause status. Methods and Results- A cohort of 150 free-living subjects was followed prospectively over a 2½-year period. BF% was measured using dual energy X-ray absorptiometry (DEXA), while BW was determined with a calibrated, electronic scale. There was no significant relationship between changes in BF% and CRP, regardless of age, initial BW, and menopause status. However, changes in BW were predictive of changes in CRP (F=7.75, p=0.006, R2=0.05). The association remained significant after adjusting for differences in baseline age, initial BW, and menopause status (F=9.17, p=0.003, R2=0.08). Conclusions- Changes in BF% are not predictive of changes in CRP. However, in agreement with other studies, variations in BW are predictive of changes in CRP. Evidently, changes in CRP are more a function of changes in BW than changes in BF% in middle-aged women. If a causal relationship is assumed, then weight gain over time is likely to increase risk of elevated CRP levels and possibly cardiovascular disease.

Two thirds of American adults are overweight and almost half of those qualify as obese. Obesity independently increases risk for cardiovascular disease (CVD), type II diabetes (T2D), and hypertension; thus, strategies to reduce risk in this population are desperately needed. Oxidative stress and inflammation are two perpetuators of these chronic diseases that are often elevated in obesity. Interventions that target reductions in oxidative stress and inflammation may help to reduce co-morbidities associated with obesity. Weight loss is shown to reduce oxidative stress and inflammation. However, the composition of and food choices within the weight loss diet may influence the response of these factors to weight loss, and has not been adequately assessed. We first tested whether there were differential effects of a conventional low-fat, high carbohydrate weight loss diet (LF) and the Atkins diet (a popular low carbohydrate, high fat diet (HF)) on oxidative stress and inflammation. We demonstrated that HF raised C-reactive protein (CRP) levels relative to LF in overweight and obese women over four weeks. This finding raises questions as to the long term safety of the HF eating plan in terms of CVD risk. We next examined the role of oxidative stress in the HF diet-induced increase in inflammation by evaluating the effects of an antioxidant supplement versus a placebo in conjunction with HF in overweight and obese men and women. Although our full hypothesis was not supported, as oxidative stress did not increase with HF, the trend for a differential effect on CRP when antioxidants were consumed is provocative. It suggests that future research on the connection between oxidative stress, the macronutrient content of the diet, and inflammation in obesity is warranted. Regarding the effects of specific fats, epidemiological research shows that diets high in saturated fat (SFA) are associated with higher CVD risk while diets higher in omega 3 fats (n-3FA) with lower CVD risk. However, the acute effects of these fats on indices of inflammation and oxidative stress are less understood, particularly in the overweight/obese population. As the majority of the time is spent in the postprandial state, the acute responses to high fat meals are gaining attention for their contribution to endothelial dysfunction and CVD. We showed that acute meals high in SFA increased a marker of endothelial activation (ICAM-1) which could contribute to the atherogenic associations with SFA. Conversely, including n-3FA in a high fat meal acutely enhanced NF-κB activation in circulating mononuclear cells; however, there were no increases in any inflammatory proteins measured over the 6 h postprandial period. It is apparent that dietary macronutrients can influence factors associated with chronic disease in overweight and obese individuals. The evidence presented here may help to refine dietary recommendations for this population. / Ph. D.

Purpose: Clinical, epidemiological and basic research evidence supports the inclusion of regular physical activity as a tool for the prevention of chronic disease and the enhancement of overall health. Cardiovascular disease (CVD), the number one cause of death in the United States, is more prevalent in African Americans when compared to other races. Extensive data suggests that increasing physical activity level, particularly with aerobic exercise training (AEXT), can improve modifiable risk factors (hypertension, obesity, dyslipidemia) for CVD. The common pathology for cardiovascular (CV) risk factors is atherosclerosis. Central to the complex pathology of atherosclerosis is the vascular endothelium. In recent years, autocrine and paracrine endothelial biomarkers that directly affect endothelial status (activated vs. inactivated) have been implicated in the pathogenesis of the development and progression of CVD and its precursors. Exercise interventions have been used to modify the concentrations of endothelial biomarkers in populations with varying disease states. The purpose of this study was to identify plasma and urinary biomarkers that are associated with aerobic capacity (VO2max) in a sedentary African American population and further determine the effect of 6-months of AEXT on the concentration and activity of the biomarkers. Methods: Participants were recruited from the Philadelphia, PA area. Twenty two pre-hypertensive African Americans (SBP 122.15±10.33, DBP 77.00±5.88; 52.27±6.25 years of age) were included. Routine fasting blood samples were drawn to assess blood lipids and fasting blood glucose along with urinalysis to rule out kidney dysfunction or disease. Subjects had a physical examination and BP measured under standardized conditions. Exclusion criteria included smoking, a body mass index (BMI) > 40 kg/m2, alcohol intake of more than 3 drinks per day, diabetes (fasting glucose level >126 mg/dl), total cholesterol >240 mg/dl, renal or CV disease. On a separate day, a sub-maximal graded exercise test with gas analysis was conducted to determine aerobic capacity. VO2max was estimated from the baseline submaximal graded exercise test. Regression analysis was used to calculate VO2max. Participants underwent 6 months of AEXT at a prescribed 3 sessions per week for 40 minutes at 65% VO2max. Plasma biomarkers of oxidative stress (8-isoprostane PGF2a), cellular activation (VCAM-1), anti-oxidants (SOD), vascular tone (NO) and anti-thrombosis (2,3 dinor 6-keto Prostaglandin F1a) were measured before and after AEXT by commercially available EIA and ELISA kits. CRP, a biomarker of systemic inflammation and predictor of CV events was assessed. Results: Estimated VO2max values confirmed that the exercise group was untrained (VO2max: 25.31 ± 3.91 ml/kg/min). At baseline the most significant correlations observed were between VO2max and CRP (r= -.50, p= .01) as well as CRP and 8-isoprostane PGF2a (r= .88, p2max and CRP remained statistically significant (r= -.46, p= .02). Nitric oxide and VCAM-1 concentrations significantly differed following the AEXT intervention (NO: pre 24.07 ± 8.80 µmol/L, NO: post 37.17 ± 15.57 µmol/L, p Conclusions: Elevated basal plasma VCAM-1, CRP and 8- isoprostane PGF2α levels are evidence of endothelial activation and systemic inflammation. Pre-intervention findings provide evidence that having a higher VO2max was strongly associated with decreased concentrations of CRP, a marker of systemic inflammation that is highly associated with risk for CVD. Post-intervention analysis suggests 6-months of AEXT is an appropriate intervention for elevating NO and decreasing VCAM-1 concentrations. This suggests there were cardioprotective modifications in the endothelial phenotype. The absence of significant change in SOD activity, 2,3 dinor 6-keto Prostaglandin F1a and CRP concentrations may suggest that AEXT is not a suitable mechanism to elicit improvements in all metabolic pathways that impact the state of the endothelium in previously sedentary African Americans. / Kinesiology

Thesis (Ph. D.)--University of Texas Health Science Center at Houston, School of Public Health, 2007. / "December 2007." Source: Dissertation Abstracts International, Volume: 68-11, Section: B, page: 7222. Adviser: Zuber D. Mulla. Includes bibliographical references (leaves 157-169).

Background: The 5 subunits of native pentameric C-reactive protein (CRP) are dissociated to generate the monomeric form of CRP (mCRP) in some in vitro conditions, both physiological and non-physiological, and also in vivo. Many bioactivities of mCRP generated by urea-treatment of CRP and of mCRP generated by mutating the primary structure of CRP have been reported. The bioactivities of mCRP generated by spontaneous dissociation of CRP are largely unexplored. Methods: We purified mCRP generated by spontaneous dissociation of CRP and investigated the binding of mCRP to enzymatically-modified low-density lipoprotein (E-LDL). Results: mCRP was approximately 60 times more potent than CRP in binding to E-LDL. In the presence of the small-molecule compound phosphoethanolamine (PEt), at 37 °C, the binding of mCRP to E-LDL was enhanced <2-fold, while the binding of CRP to E-LDL was enhanced >10-fold. In contrast, PEt inhibited the binding of both CRP and mCRP to pneumococcal C-polysaccharide, another phosphocholine-containing ligand to which CRP and mCRP were found to bind. We have not investigated yet whether PEt alters the structure of CRP at 37 °C. Conclusions: Combined data suggest that the targeting of CRP with the aim to monomerize CRP in vivo may be an effective approach to capture modified forms of LDL.