Association between serum level of urate and subclinical atherosclerosis : results from the SCAPIS Pilot

Background: Hyperuricemia is closely associated with cardiovascular disease (CVD). However, it has not been definitively established whether this association is independent of traditional cardiovascular risk factors (CVRFs) and whether it is gender-dependent. The aim of this study was to investigate in a population-based cohort (age range, 50-64 years) stratified by sex the association between the serum urate (SU) concentration and subclinical atherosclerosis, as reflected in the coronary artery calcification (CAC) score, common carotid intima-media thickness (CIMT), and carotid plaque score. Methods: The study involved participants in the Swedish CArdioPulmonary bioImage Study (SCAPIS) Pilot cohort (N = 1040; 48.8% males). This pilot cohort is part of the large population-based SCAPIS with 30,000 participants in the age range of 50-64 years, aimed at improving risk prediction for CVD. Subjects with a self-reported previous history of CVD (N = 68) or gout (N = 3) were excluded. The CAC score was assessed with the Agatston method using computed tomography. CIMT and carotid plaques were quantified by ultrasound. The associations between the SU quartiles and different levels of CAC, CIMT, and carotid plaques were assessed by multivariable logistic regression. Results: Age, BMI, education level, smoking, physical activity, hs-CRP, hypertension, and dyslipidemia showed no differences between males and females, while CAC (score > 0) and diabetes were both twice as common in men than in women (58% vs 26% and 8% vs 4%, respectively). Higher SU quartiles were in both sexes associated with BMI, hs-CRP, and the prevalence of hypertension, and in women, they were also associated with the prevalence of dyslipidemia. The three upper quartiles of SU (>308 mu mol/L) were linked to higher CAC scores in men, when adjusting for CVRFs, but not in women. CIMT and carotid plaques showed no correlation to SU in either sex. Conclusions: Higher levels of SU are associated with the presence of CAC in men but not in women, whereas SU is not associated with CIMT or carotid plaques in either men or women. This implies that the biological effects of SU differ in men and women or that SU has varying effects on different vascular beds or during the different stages of the atherosclerotic process

Early-life risk factors for reversible and irreversible airflow limitation in young adults : findings from the BAMSE birth cohort

We aimed to determine prevalence and early-life risk factors for reversible and irreversible airflow limitation in young adults from the general population. Among young adults in their 20s, the prevalence was 5.3% for reversible airflow limitation and 2.0% for irreversible airflow limitation. While parental asthma was the only risk factor for development of reversible airflow limitation, the risk factors for development of irreversible airflow limitation were current asthma, childhood respiratory tract infections and asthma, and exposure to air pollution

Compressive loading of the murine tibia reveals site-specific micro-scale differences in adaptation and maturation rates of bone

Summary: Loading increases bone mass and strength in a site-specific manner; however, possible effects of loading on bone matrix composition have not been evaluated. Site specific structural and material properties of mouse bone were analyzed on the macro- and micro/molecular scale in the presence and absence of axial loading. The response of bone to load is heterogeneous, adapting at molecular, micro- and macro-levels. Purpose/Introduction: Osteoporosis is a degenerative disease resulting in reduced bone mineral density, structure and strength. The overall aim was to explore the hypothesis that changes in loading environment result in site-specific adaptations at molecular/micro- and macro- scale in mouse bone. Methods: Right tibiae of adult mice were subjected to well-defined cyclic axial loading for two weeks; left tibiae were used as physiologically loaded controls. The bones were analyzed with µCT (structure), reference point indentation (material properties), Raman spectroscopy (chemical) and small angle X-ray scattering (mineral crystallization and structure). Results: The cranial and caudal sites of tibiae are structurally and biochemically different within control bones. In response to loading, cranial and caudal sites increase in cortical thickness with reduced mineralization (-14% and –3%, p<0.01, respectively) and crystallinity (-1.4% and –0.3%, p<0.05 respectively). Along the length of the loaded bones, collagen content becomes more heterogeneous on the caudal site and the mineral:collagen increases distally at both sites. Conclusion: Bone structure and composition are heterogeneous, finely tuned, adaptive and site specifically responsive at the micro-scale to maintain optimal function. Manipulation of this heterogeneity may affect bone strength, relative to specific applied loads

Targeting filamin A reduces macrophage activity and atherosclerosis

Background: The actin-binding protein FLNA (filamin A) regulates signal transduction important for cell locomotion, but the role of macrophage-specific FLNA during atherogenesis has not been explored. Methods: We analyzed FLNA expression in human carotid atherosclerotic plaques by immunofluorescence. We also produced mice with Flna-deficient macrophages by breeding conditional Flna-knockout mice (Flna(o/fl)) with mice expressing Cre from the macrophage-specific lysosome M promoter (LC). Atherosclerosis in vivo was studied by transplanting bone marrow from male Flna(o/fl)/LC mice to atherogenic low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice; and by infecting Flna(o/fl) and Flna(o/fl)/LC mice with AdPCSK9 (adenoviral vector overexpressing proprotein convertase subtilisin/kexin type 9). Furthermore, C57BL/6 mice were infected with AdPCSK9 and then treated with the calpain inhibitor calpeptin to inhibit FLNA cleavage. Results: We found that macrophage FLNA expression was higher in advanced than in intermediate human atherosclerotic plaques. Flna(o/fl)/LC macrophages proliferated and migrated less than controls; expressed lower levels of phosphorylated AKT and ERK1/2; exhibited reduced foam cell formation and lipid uptake; and excreted more lipids. The deficiency of Flna in macrophages markedly reduced the size of aortic atherosclerotic plaques in both Ldlr(-/-BMT:Flnao/fl/LC) and AdPCSK9-infected Flna(o/fl)/LC mice. Intima/media ratios and numbers of CD68-positive macrophages in atherosclerotic plaques were lower in Flna-deficient mice than in control mice. Moreover, we found that STAT3 interacts with a calpain-cleaved carboxyl-terminal fragment of FLNA. Inhibiting calpain-mediated FLNA cleavage with calpeptin in macrophages reduced nuclear levels of phosphorylated STAT3, interleukin 6 secretion, foam cell formation, and lipid uptake. Finally, calpeptin treatment reduced the size of atherosclerotic plaques in C57BL/6 mice infected with AdPCSK9. Conclusions: Genetic inactivation of Flna and chemical inhibition of calpain-dependent cleavage of FLNA impaired macrophage signaling and function, and reduced atherosclerosis in mice, suggesting that drugs targeting FLNA may be useful in the treatment of atherosclerosis