Effect of glucagon-like peptide-1 (GLP-1) analogues on epicardial adipose tissue: A meta-analysis.

BACKGROUND AND AIMS: Glucagon-like peptide-1 (GLP-1) analogues reduce body fat and cardiovascular events in patients with type 2 diabetes. Accumulation of epicardial adipose tissue (EAT) is associated with increased cardio-metabolic risks and coronary events in type 2 diabetes. METHODS: A systematic review and meta-analysis were performed from Glucagon-like peptide-1 analogues therapy on type 2 diabetes patients, reporting data from changes in EAT, after searching the PubMed/MEDLINE, Embase, Science Direct, Scopus, Google Scholar, and Cochrane databases. RESULTS: It has been found a limited number of studies, a total of 4 studies (n = 160 patients with GLP-1 analogues therapy) were included in the final analysis. Pooled analysis revealed that GLP-1 analogues reduce EAT (MD: 1.83 mm [-2.50; -1.10]; P < 0.01). Compared with the patients before the treatment, the patients after the treatment had a smaller HbA1c (MD -1.10%[-1.80; -0.30]; p = 0.0143) and body mass index was reduced (MD -2.20 kg/m2[-3.70; -0.60]; p = 0.0058), GLP-1 therapy reduced low-density lipoprotein levels (MD-13.53 mg/dL [-21.74; -5.31]; p = 0.001) and reduced triglycerides levels significantly (MD -18.32 -28.20 mg/dL; -8.50); p = 0.0003). CONCLUSIONS: This meta-analysis suggests that the amount of EAT is significantly reduced in T2D patients with Glucagon-like peptide-1 analogues.

Epicardial Adipose Tissue Ceramides Are Related to Lipoprotein Lipase Activity in Coronary Artery Disease: Unfolding a Missing Link.

BACKGROUND: Epicardial adipose tissue (EAT) contributes to coronary artery disease (CAD). EAT presents a specific lipidomic signature, showing increased ceramides and other proinflammatory lipids content. Besides, LPL (lipoprotein lipase) activity in EAT would contribute to its expansion, supplying fatty acids to the tissue. Our aim was to evaluate the relations between LPL activity, regulators of LPL, and ceramides in EAT from CAD patients. METHODS: We studied patients undergoing coronary bypass graft (CAD, n=25) and patients without CAD (no CAD, n=14). EAT and subcutaneous AT (SAT) were obtained, tissue LPL activity and its regulator's expression (ANGPTL4, GPIHBP1 [glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1], and PPARγ [peroxisomal proliferator-activated receptor γ]) were assessed. Tissue lipidomes were evaluated by UHPLC-MS, in positive and negative ionization modes. RESULTS: LPL activity was higher in EAT from CAD (P<0.001), and in EAT than SAT in both groups (P<0.001). ANGPTL4 levels were lower, GPIHBP1 and PPARγ levels were higher in EAT from CAD (P<0.001). In both groups, EAT exhibited more ceramide (P=0.01), directly associated with LPL activity, being the strongest association with Cer18:1/24:1 (P<0.001). EAT Cer18:1/16:0 to Cer18:1/24:0 and Cer18:1/24:1 to 18:1/24:0 ratios were higher in CAD (P=0.03; P<0.001, respectively), the latter directly associated with LPL activity (r=0.63, P<0.001) GPIHBP1 levels (r=0.68, P<0.001), and inversely to EAT ANGPTL4 expression (r=-0.49, P=0.03). Pairwise partial correlation network showed associations among bioactive lipids and LPL and its regulators (P<0.001 in all cases). CONCLUSIONS: The association between LPL activity, total ceramide, and the atherogenic ceramide ratios highlights the importance of the enzyme and these bioactive lipids contributing to the different metabolic profile of EAT in CAD.

The antagonic behavior of GPIHBP1 between EAT and circulation does not reflect lipolytic enzymes levels in the tissue and serum from coronary patients.

BACKGROUND: Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide. Recently, triglyceride rich lipoproteins are proposed to contribute to CAD risk; its concentrations would be partly determined by lipoprotein lipase (LPL) and endothelial lipase (EL). Epicardial adipose tissue (EAT), a visceral AT surrounding myocardium and coronary arteries, emerged as an important actor in CAD; the increase in its volume could be a consequence of LPL and EL. Circulating enzymes levels would be conditioned by local tissue factors. Our aim was to evaluate LPL, EL and their regulators levels in serum and EAT from CAD patients, searching for possible parallelisms and their role in the lipoprotein profile. METHODS: In serum, EAT and subcutaneous AT (SAT) from patients undergoing coronary artery bypass graft (CABG, n = 25) or valve replacement (No CABG, n = 25), LPL, EL and glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein-1 (GPIHBP1) expression were evaluated. Besides, Apoprotein (Apo)CII, CIII and AV were determined in serum, along with lipoprotein profile. RESULTS: Insulin-resistance markers were higher in CABG (p < 0.05). Serum LPL levels were decreased (p = 0.045), while EL levels increased (p < 0.001) in CABG, without differences in EAT or SAT. Circulating GPIHBP1 concentrations were decreased in CABG (p = 0.047), while EAT GPIHBP1 expression was increased (p < 0.001). ApoCII and ApoAV concentrations were higher in CABG (p = 0.016 and p = 0.047, respectively), without differences in ApoCIII concentrations between groups. CONCLUSIONS: In EAT, LPL and EL protein levels were not changed in CAD, although GPIHBP1 protein levels were higher. EAT would be a minor contributor to the circulating levels of the enzymes.

Untargeted Lipidomics Reveals a Specific Enrichment in Plasmalogens in Epicardial Adipose Tissue and a Specific Signature in Coronary Artery Disease.

OBJECTIVE: Epicardial adipose tissue (EAT) is an active endocrine organ that could contribute to the pathophysiology of coronary artery disease (CAD) through the paracrine release of proatherogenic mediators. Numerous works have analyzed the inflammatory signature of EAT, but scarce informations on its lipidome are available. Our objective was first to study the differences between EAT and subcutaneous adipose tissue (SAT) lipidomes and second to identify the specific untargeted lipidomic signatures of EAT and SAT in CAD. Approach and Results: Subcutaneous and EAT untargeted lipidomic analysis was performed in 25 patients with CAD and 14 patients without CAD and compared with paired plasma lipidomic analysis of isolated VLDL (very low-density lipoprotein) and HDL (high-density lipoprotein). Lipidomics was performed on a C18 column hyphenated to a Q-Exactive plus mass spectrometer, using both positive and negative ionization mode. EAT and SAT had independent lipidomic profile, with 95 lipid species differentially expressed and phosphatidylethanolamine 18:1p/22:6 twenty-fold more expressed in EAT compared with SAT false discovery rate =3×10-4). Patients with CAD exhibited more ceramides (P=0.01), diglycerides (P=0.004; saturated and nonsaturated), monoglycerides (P=0.013) in their EAT than patients without CAD. Conversely, they had lesser unsaturated TG (triglycerides; P=0.02). No difference was observed in the 295 lipid species found in SAT between patients with and without CAD. Fifty-one lipid species were found in common between EAT and plasma lipoproteins. TG 18:0/18:0/18:1 was found positively correlated (r=0.45, P=0.019) in EAT and HDL and in EAT and VLDL (r=0.46, P=0.02). CONCLUSIONS: CAD is associated with specific lipidomic signature of EAT, unlike SAT. Plasma lipoprotein lipidome only partially reflected EAT lipidome.

Sampling and processing blood samples within the South American Youth/Child cARdiovascular and Environmental (SAYCARE) Study.

Obesity and overweight in children and adolescents is increasing rapidly worldwide; however, scarce data have been reported from South America countries. With the purpose of assessing hyperlipidemia, insulin resistance and chronic inflammation, the evaluation of blood biomarkers such as glucose, lipoproteins and chronic inflammation proteins is required. In the context of the SAYCARE study, in children and adolescents (3 to 18 years) from seven South American cities, our aim was to assess the impact of pre analytical conditions on different biomarkers evaluated in 474 fresh serum samples, in different country centers. We also evaluated the stability according to time and frozen storage within this study across the concordance of the results obtained from the 49 blood samples measured in three different centers. Significant correlations as well as concordance were observed in TG, Total-C, HDL-C and glucose between Buenos Aires and São Paulo. The samples evaluated in Teresina and São Paulo presented similar results, with exception of total cholesterol. We observed acceptable concordance between Buenos Aires vs São Paulo and Teresina vs São Paulo, suggesting that samples could be processed in each of these centers. This concordance is a consequence of the strict pre analytical conditions previously established in the SAYCARE study.

Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 and angiopoietin-like protein 4 are associated with the increase of lipoprotein lipase activity in epicardial adipose tissue from diabetic patients.

BACKGROUND AND AIMS: Epicardial adipose tissue (EAT) is a visceral AT, surrounding myocardium and coronary arteries. Its volume is higher in Type 2 diabetic (DM2) patients, associated with cardiovascular disease risk. Lipoprotein lipase (LPL) hydrolyses triglycerides (TG) from circulating lipoproteins, supplying fatty acids to AT, contributing to its expansion. We aimed to evaluate LPL expression and activity in EAT from DM2 and no DM2 patients, and its regulators ANGPTL4, GPIHBP1 and PPARγ levels, together with VLDLR expression and EAT LPL association with VLDL characteristics. METHODS: We studied patients undergoing coronary by-pass graft (CABG) divided into CABG-DM2 (n = 21) and CABG-noDM2 (n = 29), and patients without CABG (No CABG, n = 30). During surgery, EAT and subcutaneous AT (SAT) were obtained, in which LPL activity, gene and protein expression, its regulators and VLDLR protein levels were determined. Isolated circulating VLDLs were characterized. RESULTS: EAT LPL activity was higher in CABG-DM2 compared to CABG-noDM2 and No CABG (p=0.002 and p<0.001) and in CABG-noDM2 compared to No CABG (p=0.02), without differences in its expression. ANGPTL4 levels were higher in EAT from No CABG compared to CABG-DM2 and CABG-noDM2 (p<0.001). GPIHBP1 levels were higher in EAT from CABG-DM2 and CABG-noDM2 compared to No CABG (p= 0.04). EAT from CABG-DM2 presented higher PPARγ levels than CABG-noDM2 and No CABG (p=0.02 and p=0.03). No differences were observed in VLDL composition between groups, although EAT LPL activity was inversely associated with VLDL-TG and TG/protein index (p<0.05). CONCLUSIONS: EAT LPL regulation would be mainly post-translational. The higher LPL activity in DM2 could be partly responsible for the increase in EAT volume.

Epicardial Adipose Tissue in Cardiovascular Disease.

Cardiovascular disease (CVD) is the main cause of morbidity and mortality in industrialized countries, despite the evolution of treatments and revascularization strategies. Obesity, also accompanied by a chronic inflammatory process, is an independent risk factor for CVD. Abdominal adipose tissue is a complex, metabolically very active organ capable of producing different adipokines and hormones, responsible for endocrine-metabolic comorbidities. The epicardial adipose tissue (EAT) has not been as extensively studied as the abdominal or subcutaneous adipose tissue. However, recent evidence associates it with an increased cardiometabolic risk due to its apposition with the heart. EAT stores triglycerides to provide energy to the myocardium and is characterized by its greater ability to release and capture free fatty acids. EAT strategic localization allows a singular cross talk with cardiomyocytes and vascular wall cells. The fact that EAT produces pro-inflammatory adipokines as well as metalloproteinases and pro-oxidant substances, highlights its possible direct impact on plaque vulnerability and heart failure, being still necessary further studies of EAT behavior in CVD.

Behavior of Metalloproteinases in Adipose Tissue, Liver and Arterial Wall: An Update of Extracellular Matrix Remodeling.

Extracellular matrix (ECM) remodeling is required for many physiological and pathological processes. Metalloproteinases (MMPs) are endopeptidases which are able to degrade different components of the ECM and nucleus matrix and to cleave numerous non-ECM proteins. Among pathological processes, MMPs are involved in adipose tissue expansion, liver fibrosis, and atherosclerotic plaque development and vulnerability. The expression and the activity of these enzymes are regulated by different hormones and growth factors, such as insulin, leptin, and adiponectin. The controversial results reported up to this moment regarding MMPs behavior in ECM biology could be consequence of the different expression patterns among species and the stage of the studied pathology. The aim of the present review was to update the knowledge of the role of MMPs and its inhibitors in ECM remodeling in high incidence pathologies such as obesity, liver fibrosis, and cardiovascular disease.

High-fat diet abolishes the cardioprotective effects of ischemic postconditioning in murine models despite increased thioredoxin-1 levels.

Ischemic postconditioning (PostC) reduces infarct size in healthy experimental models. However, if protective effects of PostC are abolished during early stages of atherosclerotic and if this is related with a disbalance in mitochondrial energetics and alterations in thioredoxin-1 (Trx1) is still unknown. The objectives were to generate a murine high-fat diet (HFD)-fed model that developed in a phenotype consistent with early stages of atherosclerosis to then evaluate whether HFD exposure increased oxidative stress and consequently abolished the cardioprotection conferred by PostC. We used C57/BL6 mice fed with control diet (CD) or HFD for 12 weeks. Isolated mice hearts were subjected to 30 min of ischemia and 120 min of reperfusion (I/R group). For PostC group, after ischemia, six cycles of reperfusion/ischemia were performed (10 s per cycle) at the onset of reperfusion. In CD group, the PostC reduced infarct size (CD-I/R: 52.14 ± 2.8 vs. CD-PostC: 36.58 ± 1.8, P < 0.05) and increased phosphorylation of GSK3ß (CD-PostC: 2.341 ± 1.03 vs. CD-Baseline: 0.923 ± 0.41 AUOD, P < 0.05), and this cardioprotection was abolished in HFD-exposed mice. HFD increased hydrogen peroxide levels, produced a shift towards an oxidized intracellular environment (GSSG/GSH2), and increased Trx1 expression with higher fractions of oxidized protein. State 3 mitochondrial oxygen consumption in basal conditions decreased 24% in HFD-exposed mice and PostC improved state 3 values only in CD mice. Cellular redox state and mitochondrial bioenergetics were altered in HFD-exposed mice. We demonstrated that alterations in redox state at early stages of atherosclerosis abolished cardioprotective mechanisms, such as those induced by PostC, even with increased Trx1 levels.

Endothelial Lipase Is an Alternative Pathway for Fatty Acid Release from Lipoproteins: Evidence from a High Fat Diet Model of Obesity in Rats.

Lipoprotein lipase (LPL) and endothelial lipase (EL) are involved in lipoprotein metabolism. In insulin-resistance, their behavior is altered. Peroxisome proliferator-activated receptors (PPAR) and apoproteins (apo)CII and CIII could be partly responsible for these alterations. To evaluate this response, we assessed Lpl and Lipg expression, protein levels, and enzyme activity in adipose tissue (AT) and heart in an obesity model. Besides, we assessed the role of PPAR and apoC. Male Wistar rats were fed with standard diet (Control, n = 14) or high-fat diet (HFD, n = 14) for 14 weeks. Glucose and lipoprotein profiles were measured. Histological studies were performed in heart and epididymal AT. Lpl and Lipg were assessed by reverse transcription polymerase chain reaction (RT-qPCR), protein levels by Western Blot, and activities by radiometric assays. Cardiac and AT PPAR expression were measured by Western Blot and hepatic Apoc2 and Apoc3 mRNA by RT-qPCR. In HFD, fat deposits were observed in hearts, whereas AT presented a higher adipocyte size. In heart and AT, no differences were found in Lipg mRNA between groups, while AT Lpl mRNA and LPL protein were decreased in HFD, without differences in heart. In both tissues, EL protein levels and activity were increased and inversely associated with decreased LPL activity, being partially responsible for the atherogenic lipoprotein profile in HFD. PPARγ expression in AT was decreased in HFD, without differences in cardiac PPARδ expression and hepatic apoC mRNA. The increase in EL activity could be an alternative pathway for fatty acid release from lipoproteins and uptake in tissues with decreased LPL activity. In AT, PPARγ could be involved in enzyme regulation.

Effects of the intake of white wheat bread added with garlic and resistant starch: action on calcium bioavailability and metabolic parameters of growing Wistar rats.

Wheat bread is a widely consumed food and is suitable for the introduction of functional ingredients. The aim of this work was to study the effects of bread with garlic and resistant starch as a fiber source on physiological, metabolic, and functional parameters using an in vivo Wistar rat model. Rats were fed with three diets: a control diet prepared according to the American Institute of Nutrition (C), and two semisynthetic diets containing wheat bread (B) and wheat bread with garlic, resistant starch and calcium citrate (BGR). Fresh feces were weighed and lactobacilli (L) and Enterobacteriaceae (E) were analyzed at different times: 1, 20, 45 and 60 days. The pH of the caecal content was recorded and at the end of the study changes in the bone mineral density of total skeleton (ts BMD), femur (F-BMD), spine (S-BMD) and tibia (T-BMD) were determined. Lipoprotein profile was assessed, atherogenic indexes were calculated and malonaldehyde content was measured in the serum and liver. In relation to gut microbiota, the BGR group showed an increase in the L/E ratio with respect to the other groups which was correlated with a lower cecal pH. Besides, the BGR group presented lower weight and a more favourable metabolic profile. In relation to bone measurements, the BGR group presented higher values of ts BMC, ts BMD, F-BMD, and T-BMD than the B group. Thus, bread with resistant starch, garlic and calcium citrate showed a prebiotic effect increasing calcium bioavailability and deposition in bones, compared with wheat bread. The observed beneficial health effects allow us to consider the design of healthier breads.

Metalloproteinases in non-alcoholic fatty liver disease and their behavior in liver fibrosis.

Non-alcoholic fatty liver disease (NAFLD) is a clinical entity of high prevalence in the world characterized by fatty infiltration of liver tissue in the absence of alcohol consumption. The natural history of the disease develops in successive phases reflected in different histological stages, with 10-20% of patients developing liver cirrhosis and fibrosis. Fibrosis is a basic connective tissue lesion defined by the increase of the fibrillary extracellular matrix (ECM) components in a tissue or organ. Matrix metalloproteinases (MMPs) constitute a family of endopeptidases, which are involved in ECM and basement membranes components degradation. Fibrogenic process is characterized by altered ECM composition, associated with modifications in MMPs behavior. The active cross-talk between adipose tissue and liver can be altered in pathologies associated to insulin resistance (IR), such as NAFLD. The role of adipokines on MMPs behavior in the liver could be partly responsible of liver damage during IR. The aim of this revision is to describe the behavior of MMPs in NAFLD and its role in the associated fibrosis.

Altered expression of Aquaporin-2 in one-kidney, one-clip hypertension.

AIMS: The aim of the present study was to evaluate the regulation of Aquaporin-2 (AQP2) water channel in the kidney of one-kidney, one-clip rats (Goldblatt-1 model). In addition, some mechanisms that underlie the role of AQP2 in the Goldblatt-1 model were evaluated. MAIN METHODS: Sprague-Dawley rats were divided in three groups: control two-kidney, no clip (C, 2 K-NC); nephrectomized one-kidney, no clip (N, 1 K-NC) and Goldblatt one-kidney, one-clip (G, 1 K-1C). AQP2 expression (by westernblot, real time PCR, immunohistochemistry and immunofluorescence), vasopressin V2 receptor expression (by real time PCR), cAMP concentration, NFkB and TonEBP (cytosol to nucleus ratio) were evaluated in the renal medulla. KEY FINDINGS: AQP2 expression, V2 receptor expression and cAMP concentration were decreased in the renal medulla of 1 K-1C rats, NFkB translocation was favoured towards the nucleus suggesting its activation while TonEBP translocation was not altered in this model of hypertension. SIGNIFICANCE: In this model of hypertension the decrease of AQP2 expression could be a mechanism that counteracts the high blood pressure promoting water excretion and this may be consequence of decreased vasopressin sensitivity and/or the increased activity of NFkB at renomedullary collecting duct level. Given that renovascular hypertension is among the most common causes of secondary hypertension, it is important to elucidate all the relevant mechanisms involved in the generation or in the compensation of the hypertensive state in order to improve the diagnoses and treatment of the patients.

Vitamin D is Related to Markers of Vulnerable Plaque in Acute Myocardial Infarction.

BACKGROUND: Vitamin D is a fat soluble vitamin involved in calcium and bone metabolism; recently its deficiency has been related to cardiovascular disease. In cardiac tissue, vitamin D suppresses metalloproteinases (MMPs) expression, enzymes directly associated with vulnerable plaque. OBJECTIVE: To investigate whether the association between vitamin D and leptin is related to markers of vulnerable plaque, such as MMPs in patients with acute myocardial infarction. METHODS: We studied 66 male patients with acute myocardial infarction, undergoing primary angioplasty. Blood samples were obtained at admission and 24hs after the surgery. Leptin and vitamin D concentrations in serum and MMP-2 and -9 activities in plasma were determined. RESULTS: MMP-2 activity was increased in Vitamin D deficient/insufficient patients at admission (p=0.04) and 24 hs later (p=0.05). In a linear regression model, vitamin D explained 24% of the variance of MMP-2 activity (F=2.839 p=0.04). At admission, vitamin D correlated with serum leptin (r=-0.302 p=0.033), and explained 39.5% of its variation (F=4.432 p=0.003). CONCLUSION: In the studied population, vitamin D was inversely related to MMP-2 and leptin which are involved in coronary artery disease and acute myocardial infarction. The decrease in this hormone levels would be associated with a worse metabolic profile in acute coronary syndrome patients.

Metalloproteinase 2 and 9 Activity Increase in Epicardial Adipose Tissue of Patients with Coronary Artery Disease.

BACKGROUND: Epicardial adipose tissue (EAT) is a visceral adipose tissue (AT) surrounding and infiltrating myocardium and coronary arteries. Increased EAT may represent a chronic inflammatory injury and a link with coronary artery disease (CAD). Metalloproteinases (MMPs) are involved in expansion of AT. OBJECTIVE: To evaluate MMP-2 and -9 behaviour in EAT from CAD patients. METHODS: In EAT and subcutaneous AT (SAT) from patients undergoing coronary artery bypass graft (CABG, n=26) or valve replacement (No CABG, n=18), MMP-2 and -9 activity and localization, inflammatory cells and vascular endothelial growth factor (VEGF) levels were determined. RESULTS: In EAT from CABG, MMP-2 and -9 activity was increased compared with No CABG (p=0.041 and p=0.027, respectively) and compared with SAT (p=0.005 and p=0.048, respectively). In CABG patients EAT showed higher infiltration of macrophages and T lymphocytes than SAT (p=0.01 and p=0.002, respectively). In No CABG patients no sign of cellular retention was observed in EAT or SAT. Vascular density was higher in EAT from CABG than No CABG (p=0.015) and it was directly correlated with MMP-2 (p=0.006) and MMP-9 (p=0.02). VEGF levels in EAT were directly associated with MMP-2 (p=0.016). CONCLUSION: In EAT from CABG patients the increase of MMP-2 and -9 activity and the presence of inflammatory cells would be partially responsible for extracellular matrix (ECM) remodeling and major vascular density necessary for EAT expansion. Improved knowledge of EAT behaviour may allow to identify new therapeutic targets for the treatment of CAD.