Pathogenesis Of Cardiometabolic Disorders Research Articles

Vitamin D Status, Cardiovascular Risk Profile, and miRNA-21 Levels in Hypertensive Patients: Results of the HYPODD Study.

The vitamin D and microRNA (miR) systems may play a role in the pathogenesis of cardiometabolic disorders, including hypertension. The HYPODD study was a double-blind placebo-controlled trial aiming to assess the effects of cholecalciferol treatment in patients with well-controlled hypertension and hypovitaminosis D (25OHD levels < 50 nmol/L). In addition to this clinical trial, we also evaluated the effects of cholecalciferol and calcitriol treatment on miR-21 expression in vivo and in vitro, respectively. Changes in the cardiovascular risk profiles were evaluated in HYPODD patients treated with cholecalciferol (C-cohort) or with placebo (P-cohort). The miR-21circulating levels were measured in four C-cohort patients and five P-cohort patients. In vitro, the miR-21 levels were measured in HEK-293 cells treated with calcitriol or with ethanol vehicle control. Cholecalciferol treatment increased 25OHD levels and reduced parathormone, total cholesterol, and low-density lipoprotein cholesterol levels in C-cohort patients, whereas no significant changes in these parameters were observed in P-cohort patients. The miR-21 circulating levels did not change in the C- or the P-cohort patients upon treatment. Calcitriol treatment did not affect miR-21 levels in HEK-293 cells. In conclusion, hypovitaminosis D correction ameliorated the cardiovascular risk profiles in hypertensive patients treated with cholecalciferol but did not influence the miR-21 expression.

The low-expression variant of FABP4 is associated with cardiovascular disease in type 1 diabetes

Background and Aims: The adipokine fatty-acid binding protein 4 (FABP4) has been implicated in the pathogenesis of cardiometabolic disorders. Blocking the action of FABP4 through genetic or pharmacological means in a preclinical setting or analyzing the effects of genetically reduced expression in humans is suggested to protect against obesity-related metabolic derangements and atherosclerosis. As cardiovascular disease (CVD) is common in individuals with type 1 diabetes (T1D), we examined the role of FABP4 in complications of T1D, focusing on the low-expression promoter polymorphism (rs77878271,A>G) of the FABP4 gene.

The Low-Expression Variant of FABP4 Is Associated With Cardiovascular Disease in Type 1 Diabetes.

Fatty acid binding protein 4 (FABP4) is implicated in the pathogenesis of cardiometabolic disorders. Pharmacological inhibition or genetic deletion of FABP4 improves cardiometabolic health and protects against atherosclerosis in preclinical models. As cardiovascular disease (CVD) is common in type 1 diabetes, we examined the role of FABP4 in the development of complications in type 1 diabetes, focusing on a functional, low-expression variant (rs77878271) in the promoter of the FABP4 gene. For this, we assessed the risk of CVD, stroke, coronary artery disease (CAD), end-stage kidney disease, and mortality using Cox proportional hazards models for the FABP4 rs77878271 in 5,077 Finnish individuals with type 1 diabetes. The low-expression G allele of rs77878271 increased the risk of CVD, independent of confounders. Findings were tested for replication in 852 Danish and 3,678 Finnish individuals with type 1 diabetes. In the meta-analysis, each G allele increased the risk of stroke by 26% (P = 0.04), CAD by 26% (P = 0.006), and CVD by 17% (P = 0.003). In Mendelian randomization, a 1-SD unit decrease in FABP4 increased risk of CAD 2.4-fold. Hence, in contrast with the general population, among patients with type 1 diabetes the low-expression G allele of rs77878271 increased CVD risk, suggesting that genetically low FABP4 levels may be detrimental in the context of type 1 diabetes.

Serum total adiponectin in healthy pre-pubertal nigerian school children.

Adiponectin is an excellent insulin sensitizer. It also possesses anti-inflammatory and anti-atherogenic properties that play a crucial role in the pathogenesis of cardio-metabolic disorders. Evaluating adiponectin distribution in children and factors that modulate its blood level is critical for advancing knowledge in its future role in managing associated non-communicable diseases. To investigate the adiponectin profile in apparently healthy pre-pubertal Nigerian school children. This is a cross-sectional study comprising 125 randomly recruited pupils from eight primary schools in Nnewi located in Anambra State, Nigeria. Anthropometric values were taken and venous blood samples assayed for adiponectin using Enzyme-linked immunosorbent assay (ELISA) kits. Analysis of data was done with SPSS software version 22 and R programming software. The level of significance set at P < 0.05. We enrolled a total number of 125 children, which comprised of 68 (54.4%) males and 57 (45.6%) females with a male to female ratio of 1.2:1. The mean age of all the subjects was 7.7 ± 2.0 years. The mean serum adiponectin level of all the participants was 4.67 ± 2.2 ng/mL with a range of 1.9 ng/mL to 10.0 ng/mL. Adiponectin was slightly higher in females than males (4.93 ± 2.4 ng/mL vs 4.45 ± 2.0 ng/mL, respectively; P = 0.223). In males, an inverse relationship was observed between adiponectin and increasing age, whereas in females, a positive correlation was noted (P = 0.637 vs P = 0.639, respectively). The body mass index (BMI) correlated negatively with adiponectin in all the subjects and across both the genders, but these were not statistically significant. Adiponectin varies with sex, age and BMI in pre-pubertal Nigerian children with normal BMI. Further local studies are needed to elucidate its role in the management of associated disease states.

Codeine exerts cardiorenal injury via upregulation of adenine deaminase/xanthine oxidase and caspase 3 signaling

AimsCodeine treatment has been shown to be associated with glucolipid deregulation, though data reporting this are inconsistent and the mechanisms are not well understood. Perturbation of glutathione-dependent antioxidant defense and adenosine deaminase (ADA)/xanthine oxidase (XO) signaling has been implicated in the pathogenesis of cardiometabolic disorders. We thus, hypothesized that depletion of glutathione contents and upregulation of ADA/XO are involved in codeine-induced glucolipid deregulation. The present study also investigated whether or not codeine administration would induce genotoxicity and apoptosis in cardiac and renal tissues. Materials and methodsMale New Zealand rabbits received per os distilled water or codeine, either in low dose (4 mg/kg) or high dose (10 mg/kg) for 6 weeks. Key findingsCodeine treatment led to reduced absolute and relative cardiac and renal mass independent of body weight change, increased blood glucose, total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL-C), as well as increased atherogenic indices and triglyceride-glucose index (TyG). Codeine administration significantly increased markers of cardiac and renal injury, as well as impaired cardiorenal functions. Codeine treatment also resulted in increased cardiac and renal malondialdehyde, Advanced Glycation Endproducts (AGE) and 8-hydroxydeoxyguanosine (8-OH-dG), and myeloperoxidase (MPO), ADA, XO, and caspase 3 activities. These observations were accompanied by impaired activities of cardiac and renal proton pumps. SignificanceFindings of this study demonstrate that upregulation of ADA/XO and caspase 3 signaling are, at least partly, contributory to the glucolipid deregulation and cardiorenal injury induced by codeine.

Sodium acetate prevents nicotine-induced cardiorenal dysmetabolism through uric acid/creatine kinase-dependent pathway

BackgroundCigarette smoking or nicotine replacement therapy has been associated with cardiometabolic disorders (CMD). Hyperuricemia has been implicated in the pathogenesis of CMD and cardiorenal dysfunction. Gut microbiota-derived short chain fatty acids (SCFAs) have been reported to have beneficial glucoregulatory and cardiorenal protective effects. This study aimed at investigating the effect of acetate, a gut-derived SCFA, on nicotine-induced CMD and associated cardiorenal dysmetabolism. Materials and methodTwenty-four male Wistar rats (n = 6/group) were grouped as: vehicle (p.o.), nicotine-exposed (1.0 mg/kg; p.o.), and sodium acetate-treated (200 mg/kg; p.o.) with or without nicotine exposure daily for 6 weeks. Glucose regulation was evaluated by oral glucose tolerance test and homeostatic model assessment of insulin resistance. Cardiac and renal triacylglycerol (TG), lactate, nitric oxide (NO), uric acid (UA) levels, lactate dehydrogenase (LDH), creatine kinase (CK), adenosine deaminase (ADA), and xanthine oxidase (XO) activities were measured. ResultsThe CMD were confirmed in the nicotine-exposed rats that exhibited lower body weight, insulin resistance, endothelial dysfunction, glucose intolerance, increased cardiac and renal TG, TG/HDL-cholesterol, UA, lactate, lipid peroxidation, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, LDH, CK, ADA and XO activities. Concurrent treatment with acetate prevented nicotine-induced glucometabolic and cardiorenal alterations. ConclusionIn summary, these results implied that nicotine exposure caused glucometabolic dysregulation and surplus lipid deposit in the heart and kidney through increased UA production and CK activity. Therefore, oral acetate administration prevents cardiorenal lipotoxicity and glucometabolic dysregulation via suppression of UA production and CK activity in nicotine-exposed rats.

Ratio of serum levels of AGEs to soluble RAGE is correlated with trimethylamine-N-oxide in non-diabetic subjects

Trimethylamine (TMA), an intestinal microflora-dependent metabolite formed from phosphatidylcholine- and L-carnitine-rich food, such as red meat, is further converted to trimethylamine-N-oxide (TMAO), which could play a role in cardiometabolic disease. Red meat-derived products are one of the major environmental sources of advanced glycation end products (AGEs) that may also contribute to the pathogenesis of cardiometabolic disorders through the interaction with receptor for AGEs (RAGE). However, the relationship among AGEs, soluble form of RAGE (sRAGE) and TMAO in humans remains unclear. Non-diabetic subjects underwent a physical examination, determination of blood chemistry and anthropometric variables, including AGEs, sRAGE, TMA and TMAO. Multiple regression analyses revealed that HbA1c, uric acid and AGEs were independently associated with log TMA, whereas log AGEs to sRAGE ratio and statin non-use were independently correlated with log TMAO. Our present findings indicated that AGEs to sRAGE ratio was correlated with log TMAO, a marker of cardiometabolic disorders.

Fructose Intake, Serum Uric Acid, and Cardiometabolic Disorders: A Critical Review

There is a direct relationship between fructose intake and serum levels of uric acid (UA), which is the final product of purine metabolism. Recent preclinical and clinical evidence suggests that chronic hyperuricemia is an independent risk factor for hypertension, metabolic syndrome, and cardiovascular disease. It is probably also an independent risk factor for chronic kidney disease, Type 2 diabetes, and cognitive decline. These relationships have been observed for high serum UA levels (>5.5 mg/dL in women and >6 mg/dL in men), but also for normal to high serum UA levels (5–6 mg/dL). In this regard, blood UA levels are much higher in industrialized countries than in the rest of the world. Xanthine-oxidase inhibitors can reduce UA and seem to minimize its negative effects on vascular health. Other dietary and pathophysiological factors are also related to UA production. However, the role of fructose-derived UA in the pathogenesis of cardiometabolic disorders has not yet been fully clarified. Here, we critically review recent research on the biochemistry of UA production, the relationship between fructose intake and UA production, and how this relationship is linked to cardiometabolic disorders.

Vitamin D and cardiometabolic disorders.

Recent clinical and experimental studies suggest that vitamin D status could play a significant role in the pathogenesis of cardiometabolic disorders as well as in their clinical severity. In particular, low vitamin D levels appear to increase the risk of major cardiovascular events in apparently healthy individuals and to worsen the prognosis quoad vitam and quoad valetudinem following a cardiovascular event. The relevance of these observations is amplified by the high prevalence of vitamin D deficiency and insufficiency that affect over one billion individuals at all ages worldwide. Randomized controlled trials are currently underway in U.S., Europe and Oceania to demonstrate a cause-effect relationship by assessing the effects of vitamin D supplementation on various cardiovascular outcomes. Aim of this review is to point out the more recent advances in knowledge about the relationship between vitamin D status and the incidence, prevalence and pathogenesis of more common cardiometabolic disorders.

Lysophosphatidylinositol-GPR55 signaling in the regulation of metabolism and cardiometabolic disorders

G protein coupled receptor 55 (GPR55) was initially identified as the orphan receptor and then suggested to be the atypical non-CB1/non-CB2 cannabinoid receptor. However, later studies revealed that GPR55 is specific for lysophosphatidylinositol (LPI) synthesized from membrane phosphoinositides by phospholipases A1 or A2. Recent findings suggest that LPI-GPR55 signaling is involved in the pathogenesis of cardiometabolic disorders. GPR55 is expressed in adipose tissue, endothelial cells, inflammatory cells, and cardiomyocytes. Plasma LPI concentration and GPR55 expression in the adipose tissue are modified by nutritional status, leptin level and glucose tolerance. Ligand-activated GPR55 has anabolic effect in human adipose tissue, stimulates insulin secretion, induces hyperpolarization of endothelial cells, inhibits platelet aggregation, and increases Ca 2+ concentration in cultured cardiomyocytes. In this review the recent findings about role of GPR55 signaling in adipose tissue, metabolic homeostasis and cardiovascular system are summarized. Adipobiology 2013; 5: 23-31.

Plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, e-selectin and C-reactive protein levels in response to 4-week very-high-fructose or -glucose diets

High intake of added sweeteners is considered to have a causal role in the pathogenesis of cardiometabolic disorders. Especially, high-fructose intake is regarded as potentially harmful to cardiometabolic health. It may cause not only weight gain but also low-grade inflammation, which represents an independent risk factor for developing type 2 diabetes and cardiovascular disease. In particular, fructose has been suggested to induce plasminogen activator inhibitor-1 (PAI-1) expression in the liver and to increase circulating inflammatory cytokines. We therefore aimed to investigate, whether high-fructose diet has an impact on PAI-1, monocyte chemoattractant protein-1 (MCP-1), e-selectin and C-reactive protein (CRP) concentrations in healthy humans. We studied 20 participants (12 males and 8 females) of the TUebingen FRuctose Or Glucose study. This is an exploratory, parallel, prospective, randomized, single-blinded, outpatient, hypercaloric, intervention study. The participants had a mean age of 30.9 ± 2.1 years and a mean body mass index of 26.0 ± 0.5 kg/m(2) and they received 150 g of either fructose or glucose per day for 4 weeks. There were neither significant changes of PAI-1, MCP-1, e-selectin and CRP after fructose (n=10) and glucose (n=10) intervention nor treatment effects (all P>0.2). Moreover, we did not observe longitudinal associations of the inflammatory parameters with triglycerides, liver fat, visceral fat and body weight in the fructose group. Temporary high-fructose intake does not seem to cause inflammation in apparently healthy people in this secondary analysis of a small feeding trial.

Transient Receptor Potential Vanilloid Type-1 Channel in Cardiometabolic Protection

❙ABSTRACT❙ Transient receptor potential vanilloid type-1 channel (TRPV1) is a non-selective cation channel with a preference for calcium ions that is able to sense a vast range of endogenous physical and chemical stimuli and plays an important role in transducing the sensations of noxious heat and pain signaling. Recent studies showed that TRPV1 is widely expressed in different tissues and organs beyond the sensory nerves and has multiple biological effects that are involved in functional regulation in the pancreas, blood vessel, adipose tissue and liver. To further understand the link between TRPV1 and cardiometabolic diseases, we reviewed the role of TRPV1 in hypertension, diabetes, obesity, and dyslipidemia. This review provides new insights into the involvement of TRPV1 channels in the pathogenesis of cardiometabolic disorders and implicates this channel as a potential therapeutic target for the management of cardiometabolic diseases. (J Korean Soc Hypertens 2011;17(2):37-47)