Inducible interleukin-1 gene expression in human vascular smooth muscle cells.

Interleukin-1 (IL-1) mediates many components of generalized host response to injury and may also contribute to local vascular pathology during immune or inflammatory responses. Because altered function of smooth muscle cells (SMC) accompanies certain vascular diseases, we tested whether SMC themselves might produce this hormone. Unstimulated SMC contain little or no IL-1 mRNA. However, exposure to bacterial endotoxin caused accumulation of IL-1 mRNA in SMC cultured from human vessels. Endotoxin maximally increased IL-1 beta mRNA in SMC after 4-6 h. The lowest effective concentration of endotoxin was 10 pg/ml. 10 ng/ml produced maximal increases in IL-1 beta mRNA. Interleukin-1 alpha mRNA was detected when SMC were incubated with endotoxin under "superinduction" conditions with cycloheximide. Endotoxin-stimulated SMC also released biologically functional IL-1, measured as thymocyte costimulation activity inhibitable by anti-IL-1 antibody. Thus, human SMC can express IL-1 beta and IL-1 alpha genes, or very similar ones, and secrete biologically active product in response to a pathological stimulus. Endogenous local production of this inflammatory mediator by the blood vessel wall's major cell type could play an important early role in the pathogenesis of vasculitis and arteriosclerosis

Dietary carbohydrate modifies the inverse association between saturated fat intake and cholesterol on very low-density lipoproteins

We aimed to investigate the relationship between dietary saturated fat on fasting triglyceride (TG) and cholesterol levels, and any mediation of this relationship by dietary carbohydrate intake. Men and women in the NHLBI Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) study (n = 1036, mean age ± SD = 49 ± 16 y) were included. Mixed linear models were run with saturated fat as a predictor variable and fasting TG, very low density lipoprotein cholesterol (VLDL-C), low density cholesterol (LDL-C) and high density cholesterol (HDL-C) as separate outcome variables. Subsequent models were run which included dietary carbohydrate as a predictor variable, and an interaction term between saturated fat and carbohydrate. All models controlled for age, sex, BMI, blood pressure and dietary covariates. In models that included only saturated fat as a predictor, saturated fat did not show significant associations with fasting lipids. When carbohydrate intake and an interaction term between carbohydrates and saturated fat intake was included, carbohydrate intake did not associate with lipids, but there was an inverse relationship between saturated fat intake and VLDL-C (P = 0.01) with a significant interaction (P = 0.01) between saturated fat and carbohydrate with regard to fasting VLDL-C concentrations. Similar results were observed for fasting TG levels. We conclude that, when controlling for carbohydrate intake, higher saturated fat was associated with lower VLDL-C and TGs. This was not the case at higher intakes of carbohydrate. This has important implications for dietary advice aimed at reducing TG and VLDL-C levels

Glycated hemoglobin, fasting insulin and the metabolic syndrome in males. Cross-sectional analyses of the aragon workers health study baseline

Background and aims: Glycated hemoglobin (HbA1c) is currently used to diagnose diabetes mellitus, while insulin has been relegated to research. Both, however, may help understanding the metabolic syndrome and profiling patients. We examined the association of HbA1c and fasting insulin with clustering of metabolic syndrome criteria and insulin resistance as two essential characteristics of the metabolic syndrome. Methods: We used baseline data from 3200 non-diabetic male participants in the Aragon Workers' Health Study. We conducted analysis to estimate age-adjusted odds ratios (ORs) across tertiles of HbA1c and insulin. Fasting glucose and Homeostatic model assessment - Insulin Resistance were used as reference. Here we report the uppermost-to-lowest tertile ORs (95%CI). Results: Mean age (SD) was 48.5 (8.8) years and 23% of participants had metabolic syndrome. The ORs for metabolic syndrome criteria tended to be higher across HbA1c than across glucose, except for high blood pressure. Insulin was associated with the criteria more strongly than HbA1c and similarly to Homeostatic model assessment - Insulin Resistance (HOMA-IR). For metabolic syndrome, the OR of HbA1c was 2.68, of insulin, 11.36, of glucose, 7.03, and of HOMA-IR, 14.40. For the clustering of 2 or more non-glycemic criteria, the OR of HbA1c was 2.10, of insulin, 8.94, of glucose, 1.73, and of HOMA-IR, 7.83. All ORs were statistically significant. The areas under the receiver operating characteristics curves for metabolic syndrome were 0.670 (across HbA1c values) and 0.770 (across insulin values), and, for insulin resistance, 0.647 (HbA1c) and 0.995 (insulin). Among non-metabolic syndrome patients, a small insulin elevation identified risk factor clustering. Conclusions: HbA1c and specially insulin levels were associated with metabolic syndrome criteria, their clustering, and insulin resistance. Insulin could provide early information in subjects prone to develop metabolic syndrome

CLOCK, PER2 and BMAL1 DNA methylation: association with obesity and metabolic syndrome characteristics and monounsaturated fat intake

The circadian clock system instructs 24-h rhythmicity on gene expression in essentially all cells, including adipocytes, and epigenetic mechanisms may participate in this regulation. The aim of this research was to investigate the influence of obesity and metabolic syndrome (MetS) features in clock gene methylation and the involvement of these epigenetic modifications in the outcomes. Sixty normal-weight, overweight and obese women followed a 16-weeks weight reduction program. DNA methylation levels at different CpG sites of CLOCK, BMAL1 and PER2 genes were analyzed by Sequenom's MassARRAY in white blood cells obtained before the treatment. Statistical differences between normal-weight and overweight + obese subjects were found in the methylation status of different CpG sites of CLOCK (CpGs 1, 5-6, 8 and 11-14) and, with lower statistical significance, in BMAL1 (CpGs 6-7, 8, 15 and 16-17). The methylation pattern of different CpG sites of the three genes showed significant associations with anthropometric parameters such as body mass index and adiposity, and with a MetS score. Moreover, the baseline methylation levels of CLOCK CpG 1 and PER2 CpGs 2-3 and 25 correlated with the magnitude of weight loss. Interestingly, the percentage of methylation of CLOCK CpGs 1 and 8 showed associations with the intake of monounsaturated and polyunsaturated fatty acids. This study demonstrates for the first time an association between methylation status of CpG sites located in clock genes (CLOCK, BMAL1 and PER2) with obesity, MetS and weight loss. Moreover, the methylation status of different CpG sites in CLOCK and PER2 could be used as biomarkers of weight-loss success, particularly CLOCK CPGs 5-6

High-fat meal effect on LDL, HDL, and VLDL particle size and number in the Genetics of Lipid-Lowering drugs and diet network (GOLDN): an interventional study

<p>Abstract</p> <p>Background</p> <p>Postprandial lipemia (PPL) is likely a risk factor for cardiovascular disease but these changes have not been well described and characterized in a large cohort. We assessed acute changes in the size and concentration of total and subclasses of LDL, HDL, and VLDL particles in response to a high-fat meal. Participants (n = 1048) from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study who ingested a high-fat meal were included in this analysis. Lipids were measured at 0 hr (fasting), 3.5 hr, and 6 hr after a standardized fat meal. Particle size distributions were determined using nuclear magnetic resonance spectroscopy. Analyses were stratified by baseline triglycerides (normal vs. elevated) and gender. The effect of PPL on changes in lipoprotein subclasses was assessed using repeated measures ANOVA.</p> <p>Results</p> <p>Postprandially, LDL-C, HDL-C, VLDL-C, and triglycerides increased regardless of baseline triglyceride status, with the largest increases in VLDL-C and TG; however, those with elevated triglycerides demonstrated larger magnitude of response. Total LDL particle number decreased over the 6-hour time interval, mostly from a decrease in the number of small LDL particles. Similarly, total VLDL particle number decreased due to reductions in medium and small VLDL particles. Large VLDL particles and chylomicrons demonstrated the largest increase in concentration. HDL particles demonstrated minimal overall changes in total particle number.</p> <p>Conclusions</p> <p>We have characterized the changes in LDL and VLDL particle number, and their subclass patterns following a high-fat meal.</p

Single cell profiling of COVID-19 patients: an international data resource from multiple tissues

In late 2019 and through 2020, the COVID-19 pandemic swept the world, presenting both scientific and medical challenges associated with understanding and treating a previously unknown disease. To help address the need for great understanding of COVID-19, the scientific community mobilized and banded together rapidly to characterize SARS-CoV-2 infection, pathogenesis and its distinct disease trajectories. The urgency of COVID-19 provided a pressing use-case for leveraging relatively new tools, technologies, and nascent collaborative networks. Single-cell biology is one such example that has emerged over the last decade as a powerful approach that provides unprecedented resolution to the cellular and molecular underpinnings of biological processes. Early foundational work within the single-cell community, including the Human Cell Atlas, utilized published and unpublished data to characterize the putative target cells of SARS-CoV-2 sampled from diverse organs based on expression of the viral receptor ACE2 and associated entry factors TMPRSS2 and CTSL (Muus et al., 2020; Sungnak et al., 2020; Ziegler et al., 2020). This initial characterization of reference data provided an important foundation for framing infection and pathology in the airway as well as other organs. However, initial community analysis was limited to samples derived from uninfected donors and other previously-sampled disease indications. This report provides an overview of a single-cell data resource derived from samples from COVID-19 patients along with initial observations and guidance on data reuse and exploration

Genetic risk scores associated with baseline lipoprotein subfraction concentrations do not associate with their responses to fenofibrate

Lipoprotein subclass concentrations are modifiable markers of cardiovascular disease risk. Fenofibrate is known to show beneficial effects on lipoprotein subclasses, but little is known about the role of genetics in mediating the responses of lipoprotein subclasses to fenofibrate. A recent genomewide association study (GWAS) associated several single nucleotide polymorphisms (SNPs) with lipoprotein measures, and validated these associations in two independent populations. We used this information to construct genetic risk scores (GRSs) for fasting lipoprotein measures at baseline (pre-fenofibrate), and aimed to examine whether these GRSs also associated with the responses of lipoproteins to fenofibrate. Fourteen lipoprotein subclass measures were assayed in 817 men and women before and after a three week fenofibrate trial. We set significance at a Bonferroni corrected alpha &lt;0.05 (p &lt; 0.004). Twelve subclass measures changed with fenofibrate administration (each p = 0.003 to &lt;0.0001). Mixed linear models which controlled for age, sex, body mass index (BMI), smoking status, pedigree and study-center, revealed that GRSs were associated with eight baseline lipoprotein measures (p &lt; 0.004), however no GRS was associated with fenofibrate response. These results suggest that the mechanisms for changes in lipoprotein subclass concentrations with fenofibrate treatment are not mediated by the genetic risk for fasting levels

Guidelines for training in cardiovascular magnetic resonance (CMR)

These "Guidelines for training in Cardiovascular Magnetic Resonance" were developed by the Certification Committee of the Society for Cardiovascular Magnetic Resonance (SCMR) and approved by the SCMR Board of Trustees