Endothelial ADAM10 controls cellular response to oxLDL and its deficiency exacerbates atherosclerosis with intraplaque hemorrhage and neovascularization in mice.

Introduction: The transmembrane protease A Disintegrin And Metalloproteinase 10 (ADAM10) displays a "pattern regulatory function," by cleaving a range of membrane-bound proteins. In endothelium, it regulates barrier function, leukocyte recruitment and angiogenesis. Previously, we showed that ADAM10 is expressed in human atherosclerotic plaques and associated with neovascularization. In this study, we aimed to determine the causal relevance of endothelial ADAM10 in murine atherosclerosis development in vivo. Methods and results: Endothelial Adam10 deficiency (Adam10 ecko ) in Western-type diet (WTD) fed mice rendered atherogenic by adeno-associated virus-mediated PCSK9 overexpression showed markedly increased atherosclerotic lesion formation. Additionally, Adam10 deficiency was associated with an increased necrotic core and concomitant reduction in plaque macrophage content. Strikingly, while intraplaque hemorrhage and neovascularization are rarely observed in aortic roots of atherosclerotic mice after 12 weeks of WTD feeding, a majority of plaques in both brachiocephalic artery and aortic root of Adam10ecko mice contained these features, suggestive of major plaque destabilization. In vitro, ADAM10 knockdown in human coronary artery endothelial cells (HCAECs) blunted the shedding of lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1) and increased endothelial inflammatory responses to oxLDL as witnessed by upregulated ICAM-1, VCAM-1, CCL5, and CXCL1 expression (which was diminished when LOX-1 was silenced) as well as activation of pro-inflammatory signaling pathways. LOX-1 shedding appeared also reduced in vivo, as soluble LOX-1 levels in plasma of Adam10ecko mice was significantly reduced compared to wildtypes. Discussion: Collectively, these results demonstrate that endothelial ADAM10 is atheroprotective, most likely by limiting oxLDL-induced inflammation besides its known role in pathological neovascularization. Our findings create novel opportunities to develop therapeutics targeting atherosclerotic plaque progression and stability, but at the same time warrant caution when considering to use ADAM10 inhibitors for therapy in other diseases.

Socio-demographic parameters and non-cardiac comorbidity related to self-perceived quality of life in young adults after neonatal arterial switch operation for transposition of the great arteries.

Evaluating the relation of non-cardiac comorbidity and socio-demographic factors to physical and mental health-related quality of life (QOL) which has been partially found at elevated risk in young adults after neonatal arterial switch operation (ASO) for transposition of the great arteries (TGA). In a prospective reassessment study, results of 92 unselected young adults (22.8 ± 2.6 years) having undergone evaluation of QOL (SF-36) were related to non-cardiac comorbidity with special respect to neurologic and psychiatric comorbidity and to socio-demographic parameters. Neurologic (14%) contrary to psychiatric comorbidities (6.5%) were more frequent than in the general population. The educational level was higher, the rate of unemployment was double as high compared to the average German population. Significant inverse relations (p = 0.006 to 0.033) existed between physical health domains (physical functioning and general health perception) and non-cardiac, neurologic, and psychiatric comorbidity, as well as correlations between the latter domains and socio-economic status, educational level, and worse employment status (Spearman 0.22-0.41, p < 0.0001 to 0.036). Mental health domains (vitality, social functioning, psychical health) were significantly inversely related with neurologic and psychiatric comorbidity (p = 0.002 to 0.048) and correlated with higher educational level (Spearman 0.25, p = 0.019). Neurologic and psychiatric comorbidities and socio-demographic parameters are significant risk factors for a reduced QOL concerning physical and mental health in young adults with TGA after ASO. Standardized QOL measurement should be part of routine screening programs to detect subclinical physical, neurodevelopmental, and psychosocial comorbidity.

Elucidation of the genetic causes of bicuspid aortic valve disease.

AIMS: The present study aims to characterize the genetic risk architecture of bicuspid aortic valve (BAV) disease, the most common congenital heart defect. METHODS AND RESULTS: We carried out a genome-wide association study (GWAS) including 2236 BAV patients and 11 604 controls. This led to the identification of a new risk locus for BAV on chromosome 3q29. The single nucleotide polymorphism rs2550262 was genome-wide significant BAV associated (P = 3.49 × 10-08) and was replicated in an independent case-control sample. The risk locus encodes a deleterious missense variant in MUC4 (p.Ala4821Ser), a gene that is involved in epithelial-to-mesenchymal transformation. Mechanistical studies in zebrafish revealed that loss of Muc4 led to a delay in cardiac valvular development suggesting that loss of MUC4 may also play a role in aortic valve malformation. The GWAS also confirmed previously reported BAV risk loci at PALMD (P = 3.97 × 10-16), GATA4 (P = 1.61 × 10-09), and TEX41 (P = 7.68 × 10-04). In addition, the genetic BAV architecture was examined beyond the single-marker level revealing that a substantial fraction of BAV heritability is polygenic and ∼20% of the observed heritability can be explained by our GWAS data. Furthermore, we used the largest human single-cell atlas for foetal gene expression and show that the transcriptome profile in endothelial cells is a major source contributing to BAV pathology. CONCLUSION: Our study provides a deeper understanding of the genetic risk architecture of BAV formation on the single marker and polygenic level.

Anxiety and Depression in Adults With Congenital Heart Disease.

Introduction: Anxiety and depression can worsen outcome in patients with heart disease. We elucidate the prevalence of anxiety and depression in a cohort of adults with congenital heart disease (ACHD). Materials and Methods: Prospective screening for anxiety or depression was performed in 204 consecutive patients of the outpatient clinic of our tertiary care center using the Hospital Anxiety and Depression Scale (HADS) questionnaire and the distress thermometer (DT) as a potential ultra-short screening test. Functional data were assessed at liberty of the responsible physician. HADS scores ≥ 8 were considered doubtful and scores ≥ 11 as confirmed cases of anxiety or depression, respectively. HADS results were compared with a historical group of 100 patients with non-Hodgkin Lymphoma (NHL) as well as German reference values from the literature. Results: Patients from the ACHD cohort were 28 ± 10 years old (mean ± SD, 54% male), 34% had a simple, 51% a moderate, including 52 patients with transposition of the great arteries after arterial switch operation, and 15% a heart defect of severe complexity. Prevalence of depression in ACHD was comparable to the German normal population (5.9% ACHD vs. 5.4% control). In contrast, prevalence of anxiety was higher than expected from reference values (12.7% ACHD vs. 5.6% control). There was a positive association between psychological distress and NYHA class [anxiety: OR 2.67 (95% CI, 1.50-4.76) p = 0.001; depression: OR 2.93 (95% CI, 1.60-5.35) p = 0.0005], but not with age, gender, or heart defect severity. Percentages of patients with ACHD with anxiety were significantly higher than in a cohort of patients with indolent non-Hodgkin lymphoma (NHL) but comparable to those with aggressive NHL (HADS-A ≥ 11: ACHD 12.7%, indolent NHL 2.2%, aggressive NHL 13.2%; p = 0.037 ACHD vs. indolent NHL; p = 0.929 ACHD vs. aggressive NHL). The distress thermometer screening test had only a fair discriminatory ability (AUC 0.708; p = 0.002) and is therefore of limited usability. Conclusion: Adults with congenital heart disease exhibit an increased risk for anxiety disorders independently of the severity of the underlying heart defect. Anxiety prevalence was comparable to a historical cohort of patients with aggressive NHL underlining the importance of a routine screening for psychosocial distress in adults with congenital heart disease.

The sodium-glucose co-transporter-2 inhibitor ertugliflozin modifies the signature of cardiac substrate metabolism and reduces cardiac mTOR signalling, endoplasmic reticulum stress and apoptosis.

AIM: To investigate cardiac signalling pathways connecting substrate utilization with left ventricular remodelling in a murine pressure overload model. METHODS: Cardiac hypertrophy was induced by transverse aortic constriction surgery in 20-week-old C57BL/6J mice treated with or without the sodium-glucose co-transporter 2 (SGLT2) inhibitor ertugliflozin (225 mg kg-1 chow diet) for 10 weeks. RESULTS: Ertugliflozin improved left ventricular function and reduced myocardial fibrosis. This occurred simultaneously with a fasting-like response characterized by improved glucose tolerance and increased ketone body concentrations. While cardiac insulin signalling was reduced in response to SGLT2 inhibition, AMP-activated protein kinase (AMPK) signalling was increased with induction of the fatty acid transporter cluster of differentiation 36 and phosphorylation of acetyl-CoA carboxylase (ACC). Further, enzymes responsible for ketone body catabolism (ß-hydroxybutyrate dehydrogenase, succinyl-CoA:3-oxoacid-CoA transferase and acetyl-CoA acetyltransferase 1) were induced by SGLT2 inhibition. Ertugliflozin led to more cardiac abundance of fatty acids, tricarboxylic acid cycle metabolites and ATP. Downstream mechanistic target of rapamycin (mTOR) pathway, relevant for protein synthesis, cardiac hypertrophy and adverse cardiac remodelling, was reduced by SGLT2 inhibition, with alleviation of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) providing a potential mechanism for abundant reduced left ventricular apoptosis and fibrosis. CONCLUSION: SGLT2 inhibition reduced left ventricular fibrosis in a murine model of cardiac hypertrophy. Mechanistically, this was associated with reduced cardiac insulin and increased AMPK signalling as a potential mechanism for less cardiac mTOR activation with alleviation of downstream ER stress, UPR and apoptosis.

Rare Case of an Adult With Double-Chambered Left Ventricle.

The rare case of an adult with a double-chambered left ventricle was revealed using multimodality imaging using echocardiography and cardiac magnetic resonance imaging in a 38-year-old asymptomatic male patient. The congenital malformation was dominated by a second, coarsely trabeculated muscular shelf dividing the left ventricle into 2 chambers without signs for left ventricular inflow or outflow tract obstruction. The partition wall did not show any signs for intramyocardial fibrosis in late gadolinium enhancement cardiovascular magnetic resonance imaging. Flow measurements excluded a relevant intracardial shunt across the additive perimembranous ventricular septal defect. There were no signs for global right and left ventricular dysfunction with left and right ventricular volumes and ejection fraction within normal limits. A conservative approach was recommended. In summary, we are able to present the case of an adult with a double-chambered left ventricle with a second muscular "septum" partially dividing the left ventricular cavity without causing a relevant impact on cardiac function or clinical signs for heart failure.

Le cas rare d'un adulte présentant un ventricule gauche à double chambre a été révélé par une imagerie multimodale utilisant l'échocardiographie et l'imagerie par résonnance magnétique cardiaque chez un homme asymptomatique de 38 ans. La malformation congénitale était dominée par une deuxième bande musculaire grossièrement trabéculaire divisant le ventricule gauche en deux chambres sans signes d'obstruction des chambres d'admission et d'éjection du ventricule gauche. La cloison de partition ne montrait aucun signe de fibrose intramyocardique à l'imagerie par résonnance magnétique cardiovasculaire avec rehaussement tardif au gadolinium. Les mesures du débit ont exclu un shunt intracardiaque significatif à travers le défaut septal ventriculaire transmembranaire supplémentaire. Il n'y avait pas de signe de dysfonction ventriculaire droite et gauche globale, les volumes ventriculaires gauche et droit et la fraction d'éjection étant dans les limites normales. Une approche conservatrice a été recommandée. En résumé, nous pouvons présenter le cas d'un adulte porteur d'un ventricule à double chambre avec une deuxième « cloison ¼ musculaire divisant partiellement la cavité ventriculaire gauche sans causer d'effet notable sur la fonction cardiaque ou de signes cliniques d'insuffisance cardiaque.

Late outcome, therapy and systemic ventricular function in patients with a systemic right ventricle: data of the German National Register for Congenital Heart Defects.

BACKGROUND: Adults with systemic right ventricle have a significant risk for long-term complications such as arrhythmias or heart failure. METHODS: A nationwide retrospective study based on the German National Register for Congenital Heart Disease was performed. Patients with transposition of the great arteries after atrial switch operation or congenitally corrected TGA were included. RESULTS: Two hundred and eight-five patients with transposition of the great arteries after atrial switch operation and 95 patients with congenitally corrected transposition of the great arteries were included (mean age 33 years). Systolic function of the systemic ventricle was moderately or severely reduced in 25.5 % after atrial switch operation and in 35.1% in patients with congenitally corrected transposition. Regurgitation of the systemic atrioventricular valve was present in 39.5% and 43.2% of the cases, respectively. A significant percentage of patients also had a history for supraventricular or ventricular arrhythmias. However, polypharmacy of cardiovascular drugs was rare (4.5%) and 38.5 % of the patients did not take any cardiovascular medication. The amount of cardiovascular drugs taken was associated with NYHA class as well as systemic right ventricular dysfunction. Patients with congenitally corrected transposition were more likely to receive pharmacological treatment than patients after atrial switch operation. CONCLUSION: A significant portion of patients with systemic right ventricle suffer from a relevant systemic ventricular dysfunction, systemic atrioventricular valve regurgitation, and arrhythmias. Despite this, medication for heart failure treatment is not universally used in this cohort. This emphasises the need for randomised trials in patient with systemic right ventricle.

Ventricular assist devices in paediatric cardiomyopathy and congenital heart disease: An analysis of the German National Register for Congenital Heart Defects.

BACKGROUND: Ventricular assist devices (VAD) are increasingly used in patients with end-stage heart failure due to acquired heart disease. Limited data exists on the use and outcome of this technology in children. METHODS: All children (<18 years of age) with VAD support included in the German National Register for Congenital Heart Defects were identified and data on demographics, underlying cardiac defect, previous surgery, associated conditions, type of procedure, complications and outcome were collected. RESULTS: Overall, 64 patients (median age 2.1 years; 45.3% female) receiving a VAD between 1999 and 2015 at 8 German centres were included in the analysis. The underlying diagnosis was congenital heart disease (CHD) in 25 and cardiomyopathy in 39 children. The number of reported VAD implantations increased from 13 in the time period 2000-2004 to 27 implantations in the time period 2010-2014. During a median duration of VAD support of 54 days, 28.1% of patients experienced bleeding complications (6.3% intracerebral bleeding), 14.1% thrombotic (10.9% VAD thrombosis) and 23.4% thromboembolic complications (including cerebral infarction in 18.8% of patients). Children with cardiomyopathy were more likely to receive a cardiac transplantation (79.5% vs. 28.0%) compared to CHD patients. Survival of cardiomyopathy patients was significantly better compared to the CHD cohort (p < 0.0001). Multivariate Cox-proportional analysis revealed a diagnosis of CHD (hazard ratio [HR] 4.04, p = 0.001), age at VAD implantation (HR 1.09/year, p = 0.04) and the need for pre-VAD extracorporeal membrane oxygenation (ECMO) support (HR 3.23, p = 0.03) as independent predictors of mortality. CONCLUSIONS: The uptake of VAD therapy in children is increasing. Morbidity and mortality remain high, especially in patients with congenital heart disease and those requiring ECMO before VAD implantation.

Glucagon-like peptide 1 levels predict cardiovascular risk in patients with acute myocardial infarction.

AIMS: Glucagon-like peptide 1 (GLP-1) is a gut incretin hormone inducing post-prandial insulin secretion. Glucagon-like peptide 1 levels were recently found to be increased in patients with acute myocardial infarction. Glucagon-like peptide 1 receptor agonists improve cardiovascular outcomes in patients with diabetes. The aim of this study was to assess the predictive capacity of GLP-1 serum levels for cardiovascular outcome in patients with myocardial infarction. METHODS AND RESULTS: In 918 patients presenting with myocardial infarction [321 ST-segment elevation myocardial infarction and 597 non-ST-segment elevation myocardial infarction (NSTEMI)] total GLP-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and the Global Registry of Acute Coronary Events (GRACE) score were assessed at time of hospital admission. The primary composite outcome of the study was the first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Kaplan-Meier survival plots and univariable Cox regression analyses found GLP-1 to be associated with adverse outcome [hazard ratio (HR) of logarithmized GLP-1 values: 6.29, 95% confidence interval (CI): 2.67-14.81; P < 0.0001]. After further adjustment for age, sex, family history of cardiovascular disease, smoking, diabetes, hypertension, hypercholesterinaemia, glomerular filtration rate (GFR) CKD-EPI, hs-CRP, hs-Troponin T, and NT-proBNP levels the HR remained significant at 10.98 (95% CI: 2.63-45.90; P = 0.0010). Time-dependent receiver operating characteristic curve analyses illustrated that GLP-1 levels are a strong indicator for early events. For events up to 30 days after admission, GLP-1 proved to be superior to other biomarkers including hs-Troponin T, GFR CKD-EPI, hs-CRP, and NT-proBNP. Adjustment of the GRACE risk estimate by addition of GLP-1 increased the area under the receiver operating characteristic curve over time in NSTEMI patients. CONCLUSION: In patients hospitalized for myocardial infarction, GLP-1 levels are associated with cardiovascular events.

Glucagon-Like Peptide 1 and Its Cleavage Products Are Renoprotective in Murine Diabetic Nephropathy.

Incretin-based therapies, including glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors, are potent glucose-lowering drugs. Still, only GLP-1 receptor agonists with close peptide homology to GLP-1 (liraglutide and semaglutide) but neither exenatide-based GLP-1 receptor agonists nor DPP-4 inhibitors were found to reduce cardiovascular events. This different response might relate to GLP-1 receptor-independent actions of GLP-1 caused by cleavage products only liberated by GLP-1 receptor agonists with close peptide structure to GLP-1. To test this hypothesis, we directly compared metabolic, renal, and cardiac effects of GLP-1 and its cleavage products in diabetic db/db mice. Using an adeno-associated viral vector system, we overexpressed DPP-4-resistant GLP-1 (7-37 Mut8) and the two GLP-1 cleavage products, GLP-1 (9-37) and GLP-1 (28-37), in diabetic db/db mice. Only GLP-1 (7-37 Mut8), but none of the cleavage products, significantly improved glucose metabolism. Still, all GLP-1 constructs significantly reduced tubulointerstitial renal damage, lowered expression of the tubular injury markers, and attenuated renal accumulation of macrophages and T cells. This was associated with a systemic immunomodulatory effect, which was similarly found in an acute renal ischemia/reperfusion injury model. In conclusion, GLP-1 cleavage products proved sufficient to mediate organ-protective effects, which might help to explain differences between GLP-1 receptor agonists.

Myocardial infarction is sufficient to increase GLP-1 secretion, leading to improved left ventricular contractility and mitochondrial respiratory capacity.

Myocardial infarction causes rapid impairment of left ventricular function and requires a hypercontractile response of non-infarcted tissue areas to maintain haemodynamic stability. This compensatory adaptation is mediated by humoral, inflammatory and neuronal signals. GLP-1 is an incretin hormone with glucoregulatory and cardioprotective capacities and is secreted in response to nutritional and inflammatory stimuli. Inactivation of GLP-1 is caused by the ubiquitously present enzyme DPP-4. In this study, circulating concentrations of GLP-1 were assessed after myocardial infarction and were evaluated in the light of metabolism, left ventricular contractility and mitochondrial function. Circulating GLP-1 concentrations were markedly increased in patients with acute myocardial infarction. Experimental myocardial infarction by permanent LAD ligation proved sufficient to increase GLP-1 secretion in mice. This took place in a time-dependent manner, which coincided with the capacity of DPP-4 inhibition, by linagliptin, to augment left ventricular contractility in a GLP-1 receptor-dependent manner. Mechanistically, DPP-4 inhibition increased AMPK activity and stimulated the mitochondrial respiratory capacity of non-infarcted tissue areas. We describe a new functional relevance of inflammatory GLP-1 secretion for left ventricular contractility during myocardial infarction.

The incretin hormone GIP is upregulated in patients with atherosclerosis and stabilizes plaques in ApoE-/- mice by blocking monocyte/macrophage activation.

OBJECTIVE: The incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are secreted by the gut after food intake leading to pancreatic insulin secretion and glucose lowering. Beyond its role in glucose control, GLP-1 was found in mice and men to beneficially modulate the process of atherosclerosis, which has been linked to improved cardiovascular outcome of patients with diabetes at high cardiovascular risk treated with GLP-1 receptor agonists. However, little is known on the role of the other main incretin in the cardiovascular system. The aim of this study was to characterize GIP in atherosclerotic cardiovascular disease. METHODS AND RESULTS: Serum concentrations of GIP were assessed in 731 patients who presented for elective coronary angiography at the University Hospital Aachen. While GIP concentrations were not associated with coronary artery disease (CAD), we found 97 patients with PAD (peripheral artery disease) vs. 634 without PAD to have higher circulating GIP levels (413.0 ± 315.3 vs. 332.7 ± 292.5 pg/mL, p = 0.0165). GIP levels were independently related to PAD after multivariable adjustment for CAD, age, sex, BMI, hypertension, diabetes, CRP, WBC, and smoking. To investigate the functional relevance of elevated GIP levels in human atherosclerotic disease, we overexpressed GIP (1-42) in ApoE-/- mice fed a Western diet for 12 weeks using an adeno-associated viral vector system. GIP overexpression led to reduced atherosclerotic plaque macrophage infiltration and increased collagen content compared to control (LacZ) with no change in overall lesion size, suggesting improved plaque stability. Mechanistically, we found GIP treatment to reduce MCP-1-induced monocyte migration under In vitro conditions. Additionally, GIP prevented proinflammatory macrophage activation leading to reduced LPS-induced IL-6 secretion and inhibition of MMP-9 activity, which was attributable to GIP dependent inhibition of NfκB, JNK-, ERK, and p38 in endotoxin activated macrophages. CONCLUSION: Elevated concentrations of the incretin hormone GIP are found in patients with atherosclerotic cardiovascular disease, while GIP treatment attenuates atherosclerotic plaque inflammation in mice and abrogates inflammatory macrophage activation in vitro. These observations identified GIP as a counterregulatory vasoprotective peptide, which might open new therapeutic avenues for the treatment of patients with high cardiovascular risk.

GLP-1 Levels Predict Mortality in Patients with Critical Illness as Well as End-Stage Renal Disease.

BACKGROUND: Glucagon-like peptide 1 (GLP-1) is an incretin hormone, which stimulates glucose-dependent insulin secretion from the pancreas and holds immune-regulatory properties. A marked increase of GLP-1 has been found in critically ill patients. This study was performed to elucidate the underlying mechanism and evaluate its prognostic value. METHODS: GLP-1 plasma levels were determined in 3 different patient cohorts: 1) critically ill patients admitted to our intensive care unit (n = 215); 2) patients with chronic kidney disease on hemodialysis (n = 173); and 3) a control group (no kidney disease, no acute inflammation, n = 105). In vitro experiments were performed to evaluate GLP-1 secretion in response to human serum samples from the above-described cohorts. RESULTS: Critically ill patients presented with 6.35-fold higher GLP-1 plasma level in comparison with the control group. There was a significant correlation of GLP-1 levels with markers for the severity of inflammation, but also kidney function. Patients with end-stage renal disease displayed 4.46-fold higher GLP-1 concentrations in comparison with the control group. In vitro experiments revealed a strong GLP-1-inducing potential of serum from critically ill patients, while serum from hemodialysis patients only modestly increased GLP-1 secretion. GLP-1 levels independently predicted mortality in critically ill patients and patients with end-stage renal disease. CONCLUSIONS: Chronic and acute inflammatory processes like sepsis or chronic kidney disease increase circulating GLP-1 levels. This most likely reflects a sum effect of increased GLP-1 secretion and decreased GLP-1 clearance. GLP-1 plasma levels independently predict the outcome of critically ill and end-stage renal disease patients.

The PDE4 inhibitor roflumilast reduces weight gain by increasing energy expenditure and leads to improved glucose metabolism.

AIMS: To investigate the metabolic effects of the phosphodiesterase-4 (PDE4) inhibitor roflumilast, a clinically approved anti-inflammatory drug used for the treatment of chronic obstructive pulmonary disease. MATERIALS AND METHODS: The metabolic effects of roflumilast were investigated in C57BL/6J mice, fed a high-fat Western-type diet and treated with or without roflumilast for a period of 12 weeks. RESULTS: Roflumilast led to a marked reduction in body weight gain, which became apparent in the second week after treatment initiation and was attributable to a pronounced increase in energy expenditure. Furthermore, roflumilast improved glucose tolerance, reduced insulin resistance and diminished steatohepatitis in mice. Mechanistically, this was associated with hepatic protein kinase A (PKA) and cAMP response element binding protein (CREB) activation, leading to peroxisome proliferator-activated receptor gamma coactivator-1α (PCG-1α)-dependent induction of mitochondrial biogenesis. Consistently, roflumilast increased the cellular respiratory capacity of hepatocytes in a PKA-dependent manner. CONCLUSION: Roflumilast-dependent PDE4 inhibition is a new target for weight loss strategies, especially in conditions of associated comorbidities such as insulin resistance and non-alcoholic steatohepatitis.

Interleukin-6 predicts inflammation-induced increase of Glucagon-like peptide-1 in humans in response to cardiac surgery with association to parameters of glucose metabolism.

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) is an incretin hormone, which gets secreted in response to nutritional stimuli from the gut mediating glucose-dependent insulin secretion. Interestingly, GLP-1 was recently found to be also increased in response to inflammatory stimuli in an interleukin 6 (IL-6) dependent manner in mice. The relevance of this finding to humans is unknown but has been suggested by the presence of high circulating GLP-1 levels in critically ill patients that correlated with markers of inflammation. This study was performed to elucidate, whether a direct link exists between inflammation and GLP-1 secretion in humans. RESEARCH DESIGN AND METHODS: We enrolled 22 non-diabetic patients scheduled for cardiac surgery as a reproducible inflammatory stimulus with repeated blood sampling before and after surgery. RESULTS: Mean total circulating GLP-1 levels significantly increased in response to surgery from 25.5 ± 15.6 pM to 51.9 ± 42.7 pM which was not found in a control population. This was preceded by an early rise of IL6, which was significantly associated with GLP-1 under inflammatory but not basal conditions. Using repeated measure ANCOVA, IL6 best predicted the observed kinetics of GLP-1, followed by blood glucose concentrations and cortisol plasma levels. Furthermore, GLP-1 plasma concentrations significantly predicted endogenous insulin production as assessed by C-peptide concentrations over time, while an inverse association was found for insulin infusion rate. CONCLUSION: We found GLP-1 secretion to be increased in response to inflammatory stimuli in humans, which was associated to parameters of glucose metabolism and best predicted by IL6.

[Prevention of cardiovascular disease in patients with type 2 diabetes]. / Reduktion des kardiovaskulären Risikos bei Diabetes.

The modern life style is often characterized by a lack of physical activity as well as unhealthy diet leading to a worldwide rise in obesity. This goes along with an increased incidence of type 2 diabetes, accompanied by an accelerated atherosclerosis. Life style changes and normalization of body weight therefore represent the cornerstones of diabetes prevention. In addition, a multi-factorial approach focusing on cardiovascular risk factors like dyslipidemia, hypertension and hyperglycemia enables an effective means for the prevention of micro- or macrovascular complications.

AAV-mediated gene therapy for atherosclerosis.

The prognosis of patients with coronary artery disease and stroke has improved substantially over the last decade as a result of advances in primary and secondary preventive care as well as novel interventional approaches, including the development of drug-eluting stents and balloons. Despite this progress, however, cardiovascular disease remains the leading cause of death in industrialized nations. Sustained efforts to elucidate the underlying mechanisms of atherogenesis, reperfusion-induced cardiac injury, and ischemic heart failure have led to the identification of several target genes as key players in the development and progression of atherosclerotic vascular disease. This knowledge has now enabled genetic therapeutic modulation not only for inherited diseases with a single gene defect, such as familial hypercholesterolemia, but also for multifactorial disorders. This review will focus on approaches in adeno-associated viral (AAV)-mediated gene therapy for atherosclerosis and its long-term sequelae.

The transrepressive activity of peroxisome proliferator-activated receptor alpha is necessary and sufficient to prevent liver fibrosis in mice.

UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and strongly associated with central obesity, dyslipidemia, and insulin resistance. According to the multiple-hit model of NAFLD pathogenesis, lipid accumulation drives nonalcoholic steatohepatitis (NASH) initiation by triggering oxidative stress, lipotoxicity, and subsequent activation of hepatic inflammatory responses that may progress, in predisposed individuals, to fibrosis and cirrhosis. While there is an unmet therapeutical need for NASH and fibrosis, recent preclinical studies showed that peroxisome proliferator-activated receptor (PPAR)-α agonism can efficiently oppose these symptoms. To dissect the relative contribution of antisteatotic versus anti-inflammatory PPAR-α activities in counteracting dietary-induced liver fibrosis, we used a PPAR-α mutant lacking its DNA-binding-dependent activity on fatty acid metabolism. Liver-specific expression of wild-type or a DNA-binding-deficient PPAR-α in acute and chronic models of inflammation were used to study PPAR-α's anti-inflammatory versus metabolic activities in NASH and fibrosis. Pharmacologically activated PPAR-α inhibited hepatic inflammatory responses and the transition from steatosis toward NASH and fibrosis through a direct, anti-inflammatory mechanism independent of its lipid handling properties. CONCLUSION: The transrepression activity of PPAR-α on chronic liver inflammation is sufficient to prevent progression of NASH to liver fibrosis. Dissociated PPAR-α agonists, selectively modulating PPAR-α transrepression activity, could thus be an option to prevent NASH and fibrosis progression.

GLP-1 secretion is increased by inflammatory stimuli in an IL-6-dependent manner, leading to hyperinsulinemia and blood glucose lowering.

Hypoglycemia and hyperglycemia are both predictors for adverse outcome in critically ill patients. Hyperinsulinemia is induced by inflammatory stimuli as a relevant mechanism for glucose lowering in the critically ill. The incretine hormone GLP-1 was currently found to be induced by endotoxin, leading to insulin secretion and glucose lowering under inflammatory conditions in mice. Here, we describe GLP-1 secretion to be increased by a variety of inflammatory stimuli, including endotoxin, interleukin-1ß (IL-1ß), and IL-6. Although abrogation of IL-1 signaling proved insufficient to prevent endotoxin-dependent GLP-1 induction, this was abolished in the absence of IL-6 in respective knockout animals. Hence, we found endotoxin-dependent GLP-1 secretion to be mediated by an inflammatory cascade, with IL-6 being necessary and sufficient for GLP-1 induction. Functionally, augmentation of the GLP-1 system by pharmacological inhibition of DPP-4 caused hyperinsulinemia, suppression of glucagon release, and glucose lowering under endotoxic conditions, whereas inhibition of the GLP-1 receptor led to the opposite effect. Furthermore, total GLP-1 plasma levels were profoundly increased in 155 critically ill patients presenting to the intensive care unit (ICU) in comparison with 134 healthy control subjects. In the ICU cohort, GLP-1 plasma levels correlated with markers of inflammation and disease severity. Consequently, GLP-1 provides a novel link between the immune system and the gut with strong relevance for metabolic regulation in context of inflammation.