Vasculoprotective properties of plasma lipoproteins from brown bears (Ursus arctos)

Plasma cholesterol and triglyceride (TG) levels are twice as high in hibernating brown bears (Ursus arctos) than healthy humans. Yet, bears display no signs of early stage atherosclerosis development when adult. To explore this apparent paradox, we analyzed plasma lipoproteins from the same 10 bears in winter (hibernation) and summer using size exclusion chromatography, ultracentrifugation, and electrophoresis. LDL binding to arterial proteoglycans (PGs) and plasma cholesterol efflux capacity (CEC) were also evaluated. The data collected and analyzed from bears were also compared with those from healthy humans. In bears, the cholesterol ester, unesterified cholesterol, TG, and phospholipid contents of VLDL and LDL were higher in winter than in summer. The percentage lipid composition of LDL differed between bears and humans but did not change seasonally in bears. Bear LDL was larger, richer in TGs, showed prebeta electrophoretic mobility, and had 5-10 times lower binding to arterial PGs than human LDL. Finally, plasma CEC was higher in bears than in humans, especially the HDL fraction when mediated by ABCA1. These results suggest that in brown bears the absence of early atherogenesis is likely associated with a lower affinity of LDL for arterial PGs and an elevated CEC of bear plasma

4-aminobutyrate aminotrasferase (ABAT): genetic and pharmacological evidence for an involvement in gastro esophageal reflux disease

Extent: 9p.Gastro-esophageal reflux disease (GERD) is partly caused by genetic factors. The underlying susceptibility genes are currently unknown, with the exception of COL3A1. We used three independent GERD patient cohorts to identify GERD susceptibility genes. Thirty-six families, demonstrating dominant transmission of GERD were subjected to whole genome microsatellite genotyping and linkage analysis. Five linked regions were identified. Two families shared a linked region (LOD 3.9 and 2.0) on chromosome 16. We used two additional independent GERD patient cohorts, one consisting of 219 trios (affected child with parents) and the other an adult GERD case control cohort consisting of 256 cases and 485 controls, to validate individual genes in the linked region through association analysis. Sixty six single nucleotide polymorphism (SNP) markers distributed over the nine genes present in the linked region were genotyped in the independent GERD trio cohort. Transmission disequilibrium test analysis followed by multiple testing adjustments revealed a significant genetic association for one SNP located in an intron of the gene 4-aminobutyrate aminotransferase (ABAT) (Padj = 0.027). This association did not replicate in the adult case-control cohort, possibly due to the differences in ethnicity between the cohorts. Finally, using the selective ABAT inhibitor vigabatrin (c-vinyl GABA) in a dog study, we were able to show a reduction of transient lower esophageal sphincter relaxations (TLESRs) by 57.3611.4 % (p = 0.007) and the reflux events from 3.160.4 to 0.860.4 (p = 0.007). Our results demonstrate the direct involvement of ABAT in pathways affecting lower esophageal sphincter (LES) control and identifies ABAT as a genetic risk factor for GERD.Johan Jirholt, Bengt Åsling, Paul Hammond, Geoffrey Davidson, Mikael Knutsson, Anna Walentinsson, Jörgen M. Jensen, Anders Lehmann, Lars Agreus and Maria Lagerström-Ferme

Identification of Proteins Associated with the Early Restoration of Insulin Sensitivity After Biliopancreatic Diversion

CONTEXT: Insulin resistance (IR) is a risk factor for type 2 diabetes, diabetic kidney disease, cardiovascular disease and nonalcoholic steatohepatitis. Biliopancreatic diversion (BPD) is the most effective form of bariatric surgery for improving insulin sensitivity. OBJECTIVE: To identify plasma proteins correlating with the early restoration of insulin sensitivity after BPD. DESIGN: Prospective single-center study including 20 insulin-resistant men with morbid obesity scheduled for BPD. Patient characteristics and blood samples were repeatedly collected from baseline up to 4 weeks postsurgery. IR was assessed by homeostatic model assessment for insulin resistance (HOMA-IR), Matsuda Index, and by studying metabolic profiles during meal tolerance tests. Unbiased proteomic analysis was performed to identify plasma proteins altered by BPD. Detailed plasma profiles were made on a selected set of proteins by targeted multiple reaction monitoring mass spectrometry (MRM/MS). Changes in plasma proteome were evaluated in relation to metabolic and inflammatory changes. RESULTS: BPD resulted in improved insulin sensitivity and reduced body weight. Proteomic analysis identified 29 proteins that changed following BPD. Changes in plasma levels of afamin, apolipoprotein A-IV (ApoA4), and apolipoprotein A-II (ApoA2) correlated significantly with changes in IR. CONCLUSION: Circulating levels of afamin, ApoA4, and ApoA2 were associated with and may contribute to the rapid improvement in insulin sensitivity after BPD

A Randomized Controlled Trial of Dapagliflozin Plus Once-Weekly Exenatide Versus Placebo in Individuals with Obesity and Without Diabetes : Metabolic Effects and Markers Associated with Bodyweight Loss

The sodium-glucose cotransporter 2 inhibitor dapagliflozin and the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide reduce bodyweight via differing and complementary mechanisms. This post hoc analysis investigated the metabolic effects and baseline associations with bodyweight loss on coadministration of dapagliflozin and exenatide once weekly (QW) among adults with obesity and without diabetes. In the primary trial, adults with obesity and without diabetes [n = 50; 18-70 years; body mass index (BMI) 30-45 kg/m(2)] were randomized to double-blind oral dapagliflozin 10 mg (DAPA) once daily plus subcutaneous long-acting exenatide 2 mg QW (ExQW) or placebo over 24 weeks, followed by an open-label extension from 24-52 weeks during which all participants received active treatment. Primary results have been published previously. This analysis evaluated: (1) the effects of DAPA + ExQW on changes in substrates [free fatty acids (FFAs), glycerol, beta-OH-butyrate, and glucose], hormones (glucagon and insulin), and insulin secretion [insulinogenic index (IGI)] via an oral glucose tolerance test (OGTT) and (2) associations between bodyweight loss and baseline characteristics (e.g., BMI), single-nucleotide polymorphisms (SNPs) associated with the GLP-1 pathway, and markers of glucose regulation. Compared with placebo at 24 weeks, 2-h FFAs post-OGTT increased (mean difference, +20.4 mu mol/l; P < 0.05), and fasting glucose, 2-h glucose post-OGTT, and glucose area under the concentration-time curve (AUC) decreased with DAPA + ExQW [mean differences, -0.68 mmol/l [P < 0.001], -2.20 mmol/l (P < 0.01), and -306 mmol/l min (P < 0.001), respectively]. Glucagon, glycerol, beta-OH-butyrate, and IGI did not differ by treatment group at 24 weeks. Over 52 weeks, DAPA + ExQW decreased fasting insulin, 2-h post-OGTT insulin, and insulin AUC. Among DAPA + ExQW-treated participants, for each copy of the SNP variant rs10010131 A allele (gene WFS1), bodyweight decreased by 2.4 kg (P < 0.05). Lower BMI and a lower IGI were also associated with greater bodyweight loss with DAPA + ExQW. Metabolic effects with DAPA + ExQW included less FFA suppression versus placebo during the OGTT, suggesting compensatory lipid mobilization for energy production when glucose availability was reduced because of glucosuria. The expected increase in glucagon with DAPA did not occur with DAPA + ExQW coadministration. Bodyweight loss with DAPA + ExQW was associated with the SNP variant rs10010131 A allele, lower baseline adiposity (BMI), and lower baseline insulin secretion (IGI). These findings require further validation. AstraZeneca

Transcriptomics of cardiac biopsies reveals differences in patients with or without diagnostic parameters for heart failure with preserved ejection fraction

Heart failure affects 2-3% of adult Western population. Prevalence of heart failure with preserved left ventricular (LV) ejection fraction (HFpEF) increases. Studies suggest HFpEF patients to have altered myocardial structure and functional changes such as incomplete relaxation and increased cardiac stiffness. We hypothesised that patients undergoing elective coronary bypass surgery (CABG) with HFpEF characteristics would show distinctive gene expression compared to patients with normal LV physiology. Myocardial biopsies for mRNA expression analysis were obtained from sixteen patients with LV ejection fraction >= 45%. Five out of 16 patients (31%) had echocardiographic characteristics and increased NTproBNP levels indicative of HFpEF and this group was used as HFpEF proxy, while 11 patients had Normal LV physiology. Utilising principal component analysis, the gene expression data clustered into two groups, corresponding to HFpEF proxy and Normal physiology, and 743 differentially expressed genes were identified. The associated top biological functions were cardiac muscle contraction, oxidative phosphorylation, cellular remodelling and matrix organisation. Our results also indicate that upstream regulatory events, including inhibition of transcription factors STAT4, SRF and TP53, and activation of transcription repressors HEY2 and KDM5A, could provide explanatory mechanisms to observed gene expression differences and ultimately cardiac dysfunction in the HFpEF proxy group

MCPIP1 is a novel link between diabetogenic conditions and impaired insulin secretory capacity

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Cardiac biopsies reveal differences in transcriptomics between left and right ventricle in patients with or without diagnostic signs of heart failure

Abstract New or mild heart failure (HF) is mainly caused by left ventricular dysfunction. We hypothesised that gene expression differ between the left (LV) and right ventricle (RV) and secondly by type of LV dysfunction. We compared gene expression through myocardial biopsies from LV and RV of patients undergoing elective coronary bypass surgery (CABG). Patients were categorised based on LV ejection fraction (EF), diastolic function and NT-proBNP into pEF (preserved; LVEF ≥ 45%), rEF (reduced; LVEF < 45%) or normal LV function. Principal component analysis of gene expression displayed two clusters corresponding to LV and RV. Up-regulated genes in LV included natriuretic peptides NPPA and NPPB, transcription factors/coactivators STAT4 and VGLL2, ion channel related HCN2 and LRRC38 associated with cardiac muscle contraction, cytoskeleton, and cellular component movement. Patients with pEF phenotype versus normal differed in gene expression predominantly in LV, supporting that diastolic dysfunction and structural changes reflect early LV disease in pEF. DKK2 was overexpressed in LV of HFpEF phenotype, potentially leading to lower expression levels of β-catenin, α-SMA (smooth muscle actin), and enhanced apoptosis, and could be a possible factor in the development of HFpEF. CXCL14 was down-regulated in both pEF and rEF, and may play a role to promote development of HF

Unraveling the Metabolic Derangements Occurring in Non-infarcted Areas of Pig Hearts With Chronic Heart Failure

Objective: After myocardial infarction (MI), the non-infarcted left ventricle (LV) ensures appropriate contractile function of the heart. Metabolic disturbance in this region greatly exacerbates post-MI heart failure (HF) pathology. This study aimed to provide a comprehensive understanding of the metabolic derangements occurring in the non-infarcted LV that could trigger cardiovascular deterioration. Methods and Results: We used a pig model that progressed into chronic HF over 3 months following MI induction. Integrated gene and metabolite signatures revealed region-specific perturbations in amino acid- and lipid metabolism, insulin signaling and, oxidative stress response. Remote LV, in particular, showed impaired glutamine and arginine metabolism, altered synthesis of lipids, glucose metabolism disorder, and increased insulin resistance. LPIN1, PPP1R3C, PTPN1, CREM, and NR0B2 were identified as the main effectors in metabolism dysregulation in the remote zone and were found differentially expressed also in the myocardium of patients with ischemic and/or dilated cardiomyopathy. In addition, a simultaneous significant decrease in arginine levels and altered PRCP, PTPN1, and ARF6 expression suggest alterations in vascular function in remote area. Conclusions: This study unravels an array of dysregulated genes and metabolites putatively involved in maladaptive metabolic and vascular remodeling in the non-infarcted myocardium and may contribute to the development of more precise therapies to mitigate progression of chronic HF post-MI.CC BY 4.0Correspondence:Cláudia [email protected] Synnergren [email protected]: This work was supported by AstraZeneca and the University of Skövde, Sweden under grants from the Knowledge Foundation [2014/301, 2016/294, and 2016/330]. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.</p