neuropeptide-y and Cardiovascular-Diseases

Patients with Type 2 diabetes have an excess risk for cardiovascular disease. One of the several approaches, included in the guidelines for the management of Type 2 diabetes, is based on dipeptidyl peptidase 4 (DPP-4; also termed CD26) inhibitors, also called gliptins. Gliptins inhibit the degradation of glucagon-like peptide-1 (GLP-1): this effect is associated with increased circulating insulin-to-glucagon ratio, and a consequent reduction of HbA1c. In addition to incretin hormones, there are several proteins that may be affected by DPP-4 and its inhibition: among these some are relevant for the cardiovascular system homeostasis such as SDF-1α and its receptor CXCR4, brain natriuretic peptides, neuropeptide Y and peptide YY. In this review, we will discuss the pathophysiological relevance of gliptin pleiotropism and its translational potential.

Topics: Cardiovascular Diseases; Cardiovascular System; Chemokine CXCL12; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin; Natriuretic Peptide, Brain; Neuropeptide Y; Practice Guidelines as Topic; Proteolysis; Receptors, CXCR4

Endocardial endothelial cells (EECs) constitute an important component of the heart. These cells form a monolayer that covers the cavities of the right (EECRs) and left (EECLs) ventricles. They play an important role in cardiac excitation-contraction coupling via their secretion of cardioactive factors such as neuropeptide Y (NPY). They also contribute to cardiac pathology such as arrhythmia, hypertrophy, and heart failure. Differences between EECRs and EECLs contribute to tuning of circulating factors at the entry and exit of the ventricles. NPY, via activation of its receptors, modulates the excitation-secretion coupling of EECs, thus, indirectly modulating cardiac function and remodeling.

Topics: Animals; Cardiovascular Diseases; Endocardium; Endothelial Cells; Heart Ventricles; Humans; Neuropeptide Y; Receptors, Neuropeptide Y; Signal Transduction

High levels of sympathetic drive in several cardiovascular diseases including postmyocardial infarction, chronic congestive heart failure and hypertension are reinforced through dysregulation of afferent input and central integration of autonomic balance. However, recent evidence suggests that a significant component of sympathetic hyperactivity may also reside peripherally at the level of the postganglionic neuron. This has been studied in depth using the spontaneously hypertensive rat, an animal model of genetic essential hypertension, where larger neuronal calcium transients, increased release and impaired reuptake of norepinephrine in neurons of the stellate ganglia lead to a significant tachycardia even before hypertension has developed. The release of additional sympathetic cotransmitters during high levels of sympathetic drive can also have deleterious consequences for peripheral cardiac parasympathetic neurotransmission even in the presence of β-adrenergic blockade. Stimulation of the cardiac vagus reduces heart rate, lowers myocardial oxygen demand, improves coronary blood flow, and independently raises ventricular fibrillation threshold. Recent data demonstrates a direct action of the sympathetic cotransmitters neuropeptide Y (NPY) and galanin on the ability of the vagus to release acetylcholine and control heart rate. Moreover, there is as a strong correlation between plasma NPY levels and coronary microvascular function in patients with ST-elevation myocardial infarction being treated with primary percutaneous coronary intervention. Antagonists of the NPY receptors Y1 and Y2 may be therapeutically beneficial both acutely during myocardial infarction and also during chronic heart failure and hypertension. Such medications would be expected to act synergistically with β-blockers and implantable vagus nerve stimulators to improve patient outcome.

Topics: Animals; Cardiovascular Diseases; Disease Models, Animal; Galanin; Heart; Hypertension; Neuropeptide Y; Neuropeptides; Rats; Rats, Inbred SHR; Sympathetic Nervous System

Almost 30 years ago, neuropeptide Y (NPY) was discovered as a sympathetic co-transmitter and one of the most evolutionarily conserved peptides abundantly present all over the body. Soon afterward, NPY's multiple receptors were characterized and cloned, and the peptide's role in stress was first documented. NPY has proven to be pivotal for maintaining many stress responses. Most notably, NPY is known for activating long-lasting vasoconstriction in many vascular beds, including coronary arteries. More recently, NPY was found to play a role in stress-induced accretion of adipose tissue which many times can lead to detrimental metabolic changes. It is however due to its prominent actions in the brain, one of which is its powerful ability to stimulate appetite as well as its anxiolytic activities that NPY became a peptide of importance in neuroscience. In contrast, its actions in the rest of the body, including its role as a stress mediator, remained, surprisingly underappreciated and not well understood. Our research has focused on that other, "peripheral" side of NPY. In this review, we will discuss those actions of NPY on the cardiovascular system and metabolism, as they relate to adaptation to stress, and attempt to both distinguish NPY's effects from and integrate them with the effects of the classical stress mediators, glucocorticoids, and catecholamines. To limit the bias of someone (ZZ) who has viewed the world of stress through the eyes of NPY for over 20 years, fresh insight (DH) has been solicited to more objectively assess NPY's contributions to stress-related diseases and the body's ability to adapt to stress.

Topics: Adaptation, Physiological; Animals; Cardiovascular Diseases; Cardiovascular System; History, 20th Century; Humans; Neuropeptide Y; Stress, Physiological; Sympathetic Nervous System

The increasing incidence of obesity and diabetes worldwide are critical risk factors for the development of cardiovascular disease. Although the role of the central nervous system (CNS) in the control of fat mass and glucose metabolism has been studied in detail, less is known about the contribution of neural-derived signals in the development of systemic dyslipidemia. In this review we summarize and analyze evidence suggesting a specific role of the CNS in the control of systemic cholesterol metabolism and circulating plasma lipids levels.. Although early reports based in lesions or electrical stimulation suggested a role for CNS-derived signals in the development of dyslipidemia, more recent findings have confirmed the involvement of specific neural pathways critical for the neuroendocrine control of cholesterol metabolism and plasma lipid levels.. The identification of the pathways targeted by the CNS to control plasma lipid levels could offer alternative targets to create efficient novel therapies for the treatment of several metabolic syndrome components including dyslipidemia.

Topics: Animals; Cardiovascular Diseases; Cholesterol; Humans; Lipoproteins, HDL; Lipoproteins, VLDL; Liver; Neuropeptide Y; Neurosecretory Systems

Neuropeptide Y (NPY) is a central neuromodulator and peripheral sympathetic neurotransmitter that also has important regulatory roles in cardiovascular, neuroendocrine, immune and metabolic functions during stress. Focusing on the peripheral actions of the peptide in rodent models, we summarize recent studies from our laboratory demonstrating that stress-induced release of NPY mediates accelerated atherosclerosis/restenosis, obesity and metabolic-like syndrome, particularly when combined with a high fat, high sugar diet. In this review, we propose mechanisms of NPY's actions, its receptors and cellular substrates that increase the risk for cardiovascular and metabolic diseases when chronic stress is associated with pre-existing vascular injury and/or states of hypernutrition.

Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Humans; Metabolic Diseases; Models, Biological; Neuropeptide Y; Obesity; Overnutrition; Stress, Physiological

Neuropeptide Y (NPY) is an abundant and widespread peptide in mammalian nervous system, both in the central and peripheral nervous systems. NPY is a multifunctional neurotransmitter with multiple modulator effects in the regulation of physiological functions and responses in the body. NPY is a potent orexigenic peptide, which has effects on energy balance at the level of energy intake, expenditure, and partition. There are many association studies between the NPY gene variants and cardiovascular and metabolic disease. Most of them are done by using p.L7P substitution as a marker. At the moment it seems that the p.L7P substitution of preproNPY protein causes altered NPY secretion, which leads to haemodynamic disturbances caused by sympathetic hyperactivity and to various effects caused by altered local signalling by NPY. SNP association studies using p.L7P polymorphism suggest that this functional substitution may be a strong independent risk factor for various metabolic and cardiovascular diseases.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Metabolic Diseases; Neuropeptide Y; Obesity; Polymorphism, Genetic

Neuropeptide Y (NPY) is a sympathetic neurotransmitter that acts on multiple receptors (Y1-Y6) and exerts a variety of cardiovascular effects. Originally known as a vasoconstrictor acting on Y1 receptors, NPY is also a potent angiogenic factor as well as a powerful stimulator of vascular smooth muscle proliferation and atherogenesis in vitro and in vivo. These two types of vascular remodeling are predominantly mediated by Y2/Y5 and Y1 receptors respectively, but evidence suggests that all receptors are activated in both conditions. A strategy to inhibit neointima formation and atherosclerotic lesions without impairing ischemic angiogenesis and collateral vessel formation has been a major challenge to overcome. Studies in rodents show that Y1 receptor antagonist inhibits angioplasty-induced atherosclerotic-like vascular remodeling, without affecting ischemic revascularization. Conversely, Y2 receptor activation appears to be sufficient to stimulate angiogenesis in various animal models. Thus, the use of selective receptor agonists to promote angiogenesis through the Y2 receptor while antagonizing the pro-atherosclerotic and pro-stenotic effects with Y1 receptor-selective antagonists may help to successfully treat vascular remodeling in cardiovascular diseases.

Topics: Angiogenic Proteins; Animals; Cardiovascular Diseases; Humans; Neuropeptide Y; Receptors, Neuropeptide Y; Ventricular Remodeling

Topics: Cardiovascular Diseases; Genetic Variation; Humans; Metabolic Diseases; Neuropeptide Y

I review recent knowledge on the interference of neuropeptide Y with energy balance and cardiovascular and renal disease and on the central regulation of bone mass.. Although neuropeptide Y is mainly seen as a vasoconstrictor, rats overexpressing the neuropeptide Y gene show reduced blood pressure and longer life span in comparison with control rats. Due to its strong mitogenic effects on vascular smooth muscle cells, neuropeptide Y induces occlusive lesions in a rat model of atherosclerosis induced by balloon angioplasty. The involvement of neuropeptide Y in experimental atherosclerosis is complex and may include also favourable, compensatory, mechanisms because, at physiological concentrations, it also activates a potent neoangiogenic response to ischemia. Subjects with a common genotype in the neuropeptide Y gene, which underlies increased intracellular neuropeptide Y storage, display slightly raised blood pressure, high serum cholesterol and increased carotid intima media thickness. In patients with end-stage renal disease high neuropeptide Y in plasma has been associated consistently with concentric left-ventricular hypertrophy and cardiovascular mortality. Finally, recent studies have shown that neuropeptide Y constitutes an important central regulator of bone mass and that it may be involved in inflammation and immune regulation.. Evidence has accrued in experimental animals that altered neuropeptide Y is involved in obesity and the attendant metabolic complications. Recent data also suggest that this peptide may play a role in atherosclerosis and related cardiovascular complications.

Topics: Animals; Body Weight; Bone and Bones; Cardiovascular Diseases; Energy Metabolism; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Neuropeptide Y; Rats

Topics: Animals; Anti-Obesity Agents; Cardiovascular Diseases; Humans; Neuropeptide Y; Receptors, Neuropeptide Y; Vasoconstriction; Vasodilator Agents

The historical role of noradrenaline as the predominant sympathetic neurotransmitter in vascular neuroeffector junctions has matured to include ATP and the modulator action of neuropeptide Y (NPY). Numerous studies with isolated blood vessels rings demonstrate the presence of key enzymes responsible for the synthesis of ATP, noradrenaline and NPY, their co-storage, and their electrically evoked release from sympathetic perivascular nerve terminals. Functional assays coincide to demonstrate the integral role of these neurochemicals in sympathetic reflexes. In addition, the detection of the diverse receptor populations for ATP, noradrenaline and NPY in blood vessels, either in the smooth muscle, endothelial cells or nerve endings, further contribute to the notion that sympathetic vascular reflexes encompass the orchestrated action of the noradrenaline and ATP, and their modulation by NPY. The future clinical opportunities of sympathetic co-transmission in the control of human cardiovascular diseases will be highlighted.

Topics: Adenosine Triphosphate; Animals; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Cardiovascular System; Humans; Neuroeffector Junction; Neuropeptide Y; Norepinephrine; Receptors, Neuropeptide Y; Receptors, Purinergic; Sympathetic Nervous System; Synaptic Transmission

Neuropeptide Y (NPY), a sympathetic co-transmitter, acts through multiple G protein-coupled receptors (Y1 to y6) to elicit its vast range of effects in the cardiovascular, immune, and central and peripheral nervous systems. Initially, the focus of the function of NPY in the cardiovascular system involved its acute actions, such as vasoconstriction via the Y1 receptor. However, recent studies have shown that NPY is a potent growth and angiogenic factor, which acts on multiple receptor subtypes. To be more specific, NPY-mediated vascular smooth muscle cell growth, leading to neointima formation, involves Y1 and Y1 receptors, while the angiogenic effects of NPY include Y2 and Y5 receptor activation. The presence of dipeptidyl peptidase IV also influences the cardiovascular responses of NPY by acting as a converting enzyme, shifting NPY activities away from Y1. Thus, agonists and antagonists aimed at the NPY system represent a new avenue for drug treatment, which may help alleviate several cardiovascular disorders in which vascular remodeling plays a major role, such as atherosclerosis, restenosis following balloon angioplasty, hypertension and peripheral vascular disease.

Topics: Animals; Cardiovascular Agents; Cardiovascular Diseases; Humans; Muscle, Smooth, Vascular; Neuropeptide Y; Receptors, Neuropeptide Y; Tunica Intima

The peptidic neuropeptide Y (NPY) has received great attention because it has been implicated in the regulation of several organ systems. In particular, NPY is involved in the regulatory loops that control food intake in the hypothalamus and appears also to be important for regulating the activity of neuroendocrine axes under poor metabolic conditions. Furthermore, NPY exerts vasoconstrictive action on the vasculature and potentiates the actions of many other vasoconstrictors. In addition, it was demonstrated to have trophic properties and could therefore contribute to cardiovascular remodeling. These various effects plus a number of others make NPY an attractive target for the potential treatment of human diseases, such as obesity, metabolic disorders, hypertension and heart failure.

Topics: Animals; Antihypertensive Agents; Appetite Stimulants; Cardiovascular Diseases; Cardiovascular System; Forecasting; Humans; Hypothalamus; Models, Biological; Neuropeptide Y; Neurosecretory Systems; Protein Processing, Post-Translational; Receptors, Neuropeptide Y; Signal Transduction

1. The present review covers two aspects of the author's research into the pharmacology of vascular reactivity of isolated vessels and in the intact circulation. First, how 'normal' reactivity is altered by injury or disease and, second, how novel drugs have allowed insight into the role of the cotransmitter neuropeptide Y and 'N' type calcium channels in neurotransmitter release. 2. Acute endothelium removal in the femoral artery of the anaesthetized dog confirmed the obligatory role of these cells in the dilatation response to intra-arterial acetylcholine (ACh). After 4 weeks, conduit arteries respond with a thickened neointima following acute endothelial injury but, provided macrophage-derived foam cells are absent, the artery relaxes normally to ACh. 3. In the dog coronary vasculature, stable collateral arteries have a marked neointima of non-contractile smooth muscle cells that are lined with endothelium. Reactivity to vasodilator stimuli is normal while that to vasoconstrictor stimuli is impaired. 4. In the conscious rabbit, superficial femoral artery (SFA) occlusion stimulates profound angiogenesis but, despite these changes to the hindlimb vasculature, reactivity to vasodilator and vasoconstrictor agents from day 1 to 6 months following SFA is unaltered. 5. Endothelial dysfunction is discussed in relation to hypertension, hypercholesterolaemia and congestive heart failure. 6. The novel "N' type calcium channel antagonist omega-conotoxin GVIA, was used to explore the role of "N' type channels in cardiac and vascular neurotransmitter release in conscious rabbits. 7. The novel putative Y 1-selective neuropeptide Y antagonist 1229U91 was shown to inhibit nerve-mediated contractions of isolated mesenteric, but not femoral, artery segments in the rat. This regional difference in a possible cotransmitter role of the peptide is discussed.

Topics: Animals; Blood Vessels; Calcium Channels; Cardiovascular Diseases; Collateral Circulation; Coronary Vessels; Endothelium; Muscle, Smooth, Vascular; Neovascularization, Physiologic; Neuropeptide Y

Since its discovery in 1982, neuropeptide Y (NPY) has been shown to have numerous effects mediated by a growing number of NPY receptors in both the CNS and peripheral nervous system. Perhaps best appreciated is the role of NPY in the control of systemic blood pressure, together with its effects on feeding, anxiety and memory. However, recent evidence increasingly supports an important role for NPY in mediating analgesia and hyperalgesia by distinct central and peripheral mechanisms. In this review we concentrate on this important aspect of NPY pharmacology and consider mechanisms controlling the expression of NPY and its receptors. In addition, we also present the more recent data describing the other possible roles for NPY-NPY agonists and antagonists may be useful in the treatment of conditions as varied as anorexia, epilepsy, anxiety, depression, hypertension and heart failure.

Topics: Analgesics; Animals; Anti-Anxiety Agents; Antihypertensive Agents; Appetite Stimulants; Cardiovascular Diseases; Central Nervous System; Depression; Humans; Hyperalgesia; Memory Disorders; Neuropeptide Y; Peripheral Nervous System; Receptors, Neuropeptide Y; Schizophrenia

The coexistence of neuropeptide Y (NPY) with noradrenaline (NA) in perivascular nerves as well as in sympathetic nerves to muscle in the heart, spleen and vas deferens suggests a role for NPY in autonomic transmission. Sympathetic nerve stimulation or reflexogenic activation in experimental animals or man are associated with NPY release as revealed by overflow mainly upon strong activation. This difference between NPY and NA secretion may be related to the partly separate subcellular storage whereby NPY seems to be exclusively present in the large dense-cored vesicles. The NPY secretion is likely to be regulated by the local biophase concentrations of NA acting on prejunctional alpha-2-adrenoceptors since alpha-2 agonists inhibit and antagonists enhance NPY overflow, respectively. Furthermore, after NA has been depleted by reserpine, the nerve stimulation-evoked release of NPY is enhanced leading to a progressive depletion of tissue content of NPY. Exogenous NPY binds to both pre- and postjunctional receptors, inhibits NA and NPY release, enhances NA-evoked vasoconstriction and induces vasoconstriction per se. The prejunctional action of NPY which is especially noticeable in the vas deferens may serve to reduce transmitter secretion upon excessive stimulation. The long-lasting vasoconstriction evoked by sympathetic stimulation in several tissues including skeletal muscle, nasal mucosa and spleen, which remains in animals pretreated with reserpine (to deplete NA) combined with preganglionic denervation (to prevent the concomitant excessive NPY release and depletion), is mimicked by NPY and highly correlated to NPY release. Under these circumstances the NPY content in the local venous effluent reaches levels at which exogenous NPY evokes vasoconstriction.

Topics: Cardiovascular Diseases; Electric Stimulation; Humans; Neuropeptide Y; Norepinephrine; Signal Transduction; Sympathetic Nervous System; Synaptic Transmission; Vasoconstriction

Topics: Animals; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Chromatography, High Pressure Liquid; Coronary Vessels; Dogs; Guinea Pigs; Heart; Hemodynamics; Humans; Neuropeptide Y; Rabbits; Rats; Vasoconstriction; Vasodilation

Our aim was to evaluate the relationship of weight loss and changes in adipokine levels after two hypocaloric diets in obese subjects with polymorphism rs16147 of the neuropeptide Y gene.. A population of 283 obese patients was analyzed. At the basal visit, patients were randomly allocated to one of two diets for a period of 3 months (diet I, low in carbohydrates; diet II, low in fat).. With diet I and in both genotype groups (major versus minor allele), body mass index (BMI), weight, fat mass, waist circumference, and leptin decreased. With diet II and in all genotypes, BMI, weight, fat mass, waist circumference, and leptin decreased. With both diets and in subjects with the minor allele, insulin levels (diet I: major allele -1.7 ± 7.8 IU/L versus minor allele -4.2 ± 6.1 IU/L, p = 0.01; diet II: major allele -2.3 ± 6.1 IU/L versus minor allele -4.0 ± 5.2 IU/L, p = 0.02) and insulin resistance (diet I: major allele -0.2 ± 3.1 units versus minor allele -1.7 ± 3.0 units, p = 0.03; diet II: major allele -0.9 ± 2.0 units versus minor allele -1.7 ± 1.3 units, p = 0.01) decreased.. The rs16147 genotype affected the reduction in insulin resistance and insulin levels in response to two different hypocaloric diets in obese subjects, with a lack of response in subjects with the major allele.

Topics: Adipokines; Adult; Cardiovascular Diseases; Diet, Carbohydrate-Restricted; Diet, Fat-Restricted; Diet, Reducing; Female; Genetic Markers; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Neuropeptide Y; Nutrigenomics; Obesity; Polymorphism, Single Nucleotide; Prospective Studies; Risk Factors; Weight Loss

Apolipoprotein A1 (ApoA1), a major component of high-density lipoprotein (HDL), is a protective factor against cardiovascular disease (CVD). A recent epidemiological study found an association between neuropeptide Y (NPY) gene polymorphism and serum HDL levels. However, the direct effect of NPY on ApoA1 expression remains unknown. This study was designed to investigate the molecular mechanisms underlying the NPY-mediated regulation of hepatic ApoA1.. Serum ApoA1, total cholesterol, and HDL-c and hepatic ApoA1 levels were measured after intraperitoneal administration of NPY or an NPY Y5 receptor (NPY5R) agonist in vivo. HepG2 and BRL-3A hepatocytes were treated in vitro with NPY in the presence or absence of NPY receptor antagonists, agonists, or signal transduction pathway inhibitors. Subsequently, the protein and mRNA expression of cellular and secreted ApoA1 were determined.. NPY considerably upregulated hepatic ApoA1 expression and stimulated ApoA1 secretion, both in vivo and in vitro. NPY5R inhibition blocked NPY-induced upregulation of ApoA1 expression, and NPY5R activation stimulated ApoA1 expression and secretion in hepatocytes. Moreover, extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and protein kinase A (PKA) inhibition almost completely blocked the upregulation of ApoA1 expression and secretion induced by NPY5R.. For the first time, we demonstrated that NPY5R activation promotes hepatic ApoA1 synthesis and secretion through the ERK1/2 and PKA signal transduction pathways. Thus, NPY5R may be a potential therapeutic target for treating CVD by promoting cholesterol reverse transport.

Topics: Apolipoprotein A-I; Cardiovascular Diseases; Cholesterol; Humans; Neuropeptide Y; Receptors, Neuropeptide Y

Increased activity of the sympathetic nervous system (SNS) has been proposed as a risk factor for increased cardiovascular mortality in patients with chronic kidney disease (CKD). Information on the activity of cardiac sympathetic innervation is non-homogeneous and incomplete. The aim of our study was to evaluate the tonic effect of SNS on heart rate, norepinephrine turnover and direct and indirect effects of norepinephrine in left ventricles of subtotally nephrectomized rats (SNX) in comparison with sham-operated animals (SHAM). Renal failure was verified by measuring serum creatinine and urea levels. SNX rats developed increased heart rates and blood pressure (BP). The increase in heart rate was not caused by sympathetic overactivity as the negative chronotropic effect of metipranolol did not differ between the SNX and SHAM animals. The positive inotropic effects of norepinephrine and tyramine on papillary muscle were not significantly different. Norepinephrine turnover was measured after the administration of tyrosine hydroxylase inhibitor, pargyline, tyramine, desipramine, and KCl induced depolarization. The absolute amount of released norepinephrine was comparable in both groups despite a significantly decreased norepinephrine concentration in the cardiac tissue of the SNX rats. We conclude that CKD associated with renal denervation in rats led to adaptive changes characterized by an increased reuptake and intracellular norepinephrine turnover which maintained normal reactivity of the heart to sympathetic stimulation.

Topics: Animals; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Disease Models, Animal; Heart Rate; Heart Ventricles; Kidney; Male; Nephrectomy; Neuropeptide Y; Norepinephrine; Rats, Wistar; Renal Insufficiency, Chronic; Sympathetic Nervous System

Neuropeptide Y (NPY) is a multifaceted sympathetic neurotransmitter regulating reflex cardiovascular control, myocardial cell growth, inflammation and innate immunity. Circulating NPY levels predict cardiovascular mortality in patients with end stage kidney disease on dialysis but this relationship has never been tested in predialysis chronic kidney disease (CKD) patients.. We investigated the relationship between circulating NPY and the risk for cardiovascular events (Fine & Gray competing risks model) in a cohort of 753 stages 2-5 CKD patients over a median follow-up of 36 months.. Independently of other risk factors, plasma NPY was directly related with the glomerular filtration rate (β = -0.19, P < 0.001) but was independent of systemic inflammation as quantified by serum IL6 and C reactive protein. Over follow-up 112 patients had cardiovascular events and 12 died. In analyses fully adjusted for traditional risk factors and a large series of CKD-specific risk factors and considering death as a competing event (Fine and Gray model) a 0.25 μmol/l increase in NPY robustly predicted the incident risk for cardiovascular events (subdistribution hazard ratio: 1.25; 95% confidence interval: 1.09-1.44; P = 0.002). Furthermore, the fully adjusted NPY - cardiovascular outcomes relationship was modified by age (P = 0.012) being quite strong in young patients but weaker in the old ones.. NPY is an independent, robust predictor of cardiovascular events in predialysis CKD patients and the risk for such events is age-dependent being maximal in young patients. These findings suggest that NPY may play a role in the high risk of cardiovascular disease in this population.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Cohort Studies; Female; Glomerular Filtration Rate; Humans; Incidence; Male; Middle Aged; Neuropeptide Y; Renal Insufficiency, Chronic; Risk Factors

The main genetic variant described in NPY gene is rs16147 (G-399A) and it is located within the promoter region upstream of the gene for neropeptide Y (NPY). We evaluate the effects of the rs16147 NPY gene polymorphism on metabolic changes secondary to weight loss after 3 months of a hypocaloric diet in adult obese patients.. A population of 82 obese patients was analysed in an interventional design of one arm. Before and after 3 months on a hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake and a biochemical analysis were performed. The statistical analysis was performed for combined GA and AA as a group (minor allele group) and GG as second group (major allele group) (dominant model).. In A allele carriers, the mean (SD) decrease in weight was -2.8 (2.2) kg [decrease in non A allele carriers -2.6 (1.1) kg, P > 0.05), body mass index was -1.2 (0.6) kg m. We found that the rs164147 genotype affected the reduction of waist circumference, HOMA-IR, insulin, CRP and IL-6 levels in response to weight loss diet in obese subjects.

Topics: Adipokines; Adult; Biomarkers; Blood Glucose; Body Mass Index; C-Reactive Protein; Caloric Restriction; Cardiovascular Diseases; Diet, Fat-Restricted; Diet, Reducing; Female; Follow-Up Studies; Humans; Insulin Resistance; Male; Middle Aged; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Prospective Studies; Risk Factors; Waist Circumference; Weight Loss

The NPY gene has 4 exons, and it is located at 7p15.1. The main genetic variant described in this gene is rs16147. The aim of this study was to investigate the relationship of NPY rs16147 with body weight, insulin resistance, serum adipokine levels, and risk of metabolic syndrome (MetS).. A population of 1,005 obese patients was analyzed in a cross-sectional survey. Weight, fat mass, waist circumference, blood pressure, basal glucose, C-reactive protein, insulin, insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]), lipid profile, and adipocytokine (leptin, adiponectin, and resistin) levels were measured. The genotype of the NPY gene polymorphism (rs16147) was studied.. Body mass index (1.0 ± 0.1; p < 0.05), weight (2.8 ± 0.4 kg; p < 0.05), fat mass (1.8 ± 0.3 kg; p < 0.05), waist circumference (1.9 ± 0.2 cm; p < 0.05), leptin level (15.4 ± 8.2 ng/mL; p < 0.05), insulin level (5.1 ± 1.3 mIU/L; p < 0.05), and HOMA-IR (1.4 ± 0.1 units; p < 0.05) were lower in A allele carriers than in non-A allele carriers in males. Males with an A allele had a lower percentage of MetS (54.8 vs. 69.1%; p < 0.05), central obesity (94.5 vs. 100%; p < 0.05), and hyperglycemia (24.7 vs. 33.8%; p < 0.05) than non-A allele carriers. Logistic regression analysis indicated that male non-A allele carriers had an increased risk of MetS (odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.17-1.83; p = 0.034), an increased risk of central obesity (OR = 1.08, 95% CI = 1.02-1.11; p = 0.044), and an increased risk of hyperglycemia (OR = 1.20, 95% CI = 1.09-1.79; p = 0.028) after adjusting for age.. In obese males, the rs164147 polymorphism of the NPY gene is associated with leptin, insulin level, HOMA-IR, and an increased risk of MetS and its related phenotypes, such as central obesity and hyperglycemia.

Topics: Adipokines; Adult; Cardiovascular Diseases; Cross-Sectional Studies; Female; Genetic Association Studies; Humans; Hyperglycemia; Insulin Resistance; Male; Metabolic Syndrome; Middle Aged; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Risk Factors

Neuropeptide Y (NpY) is an important factor in neuropeptide signalling, and significantly change in the blood and cerebrospinal fluid (CSF) during chronic kidney disease (CKD) progression. However, the role of NpY remains unclear. We aimed to investigate the associations between NpY levels, nutritional status and cardiovascular disease (CVD) in patients with CKD.. In this cohort study, we performed Pearson's correlation analysis and multiple linear regressions to assess the relationship between CSF and serum NpY levels, as well as nutritional indices. Receiver operating characteristic curves were used to evaluate the sensitivity and specificity of CSF NpY levels. As NpY affects the cardiovascular system, Kaplan-Meier analysis was used to investigate the relationship between serum NpY levels and CVD.. CSF NpY levels and nutritional indices were related during CKD progression (energy intake: β=0.236, P<0.001; mid-arm muscle circumference: β=0.953, P=0.014; prealbumin: β=0.067, P<0.001), and had high specificity (79.9%). High serum NpY levels may be a risk factor associated with CVD (relative risk=1.8015, 95% confidence interval: 1.0509-3.0881).. Our results suggested a relationship between CSF NpY levels and nutritional indices in CKD patients. High serum NpY concentrations may be a risk factor associated with CVD.

Topics: Adult; Aged; Biomarkers; Cardiovascular Diseases; China; Cohort Studies; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neuropeptide Y; Nutritional Status; Prognosis; Prospective Studies; Renal Insufficiency, Chronic; Risk Factors; ROC Curve; Sensitivity and Specificity; Severity of Illness Index; Up-Regulation

Variants in the neuropeptide Y (NPY) gene have been associated with obesity and its traits. The objective of the present study was to evaluate the association of single nucleotide polymorphisms (SNPs) in the NPY gene with obesity, metabolic syndrome features, and inflammatory and cardiovascular disease (CVD) risk biomarkers in Spanish children. We recruited 292 obese children and 242 normal-body mass index (BMI) children. Height, weight, BMI, waist circumference, clinical and metabolic markers, adipokines, and inflammatory (PCR, IL-6, IL-8 and TNF-α) and CVD risk biomarkers (MPO, MMP-9, sE-selectin, sVCAM, sICAM, and PAI-1) were analyzed. Seven SNPs in the NPY gene were genotyped. The results of our study indicate that anthropometric measurements, clinical and metabolic markers, adipokines (leptin and resistin), and inflammatory and CVD risk biomarkers were generally elevated in the obese group. The exceptions to this finding included cholesterol, HDL-c, and adiponectin, which were lower in the obese group, and glucose, LDL-c, and MMP-9, which did not differ between the groups. Both rs16147 and rs16131 were associated with the risk of obesity, and the latter was also associated with insulin resistance, triacylglycerols, leptin, and HDL-c. Thus, we confirm the association of rs16147 with obesity, and we demonstrate for the first time the association of rs16131 with obesity and its possible impact on the early onset of metabolic syndrome features, mainly triacylglycerols, in children.

Topics: Adolescent; Biomarkers; Body Mass Index; Cardiovascular Diseases; Case-Control Studies; Child; Child, Preschool; Cytokines; Female; Genotyping Techniques; Humans; Leptin; Male; Metabolic Syndrome; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Resistin; Risk Factors; Spain; Triglycerides; Waist Circumference

To assess whether endocrine dysfunction may cause derangement in energy homeostasis in patients undergoing hemodialysis (HD), we profiled hormones, during a 3-day period, from the adipose tissue and the gut and the nervous system around the circadian clock in 10 otherwise healthy HD patients and 8 normal controls. The protocol included a 40-h fast. We also measured energy-protein intake and output and assessed appetite and body composition. We found many hormonal abnormalities in HD patients: 1) leptin levels were elevated, due, in part, to increased production, and nocturnal surge in response to daytime feeding, exaggerated. 2) Peptide YY (PYY), an anorexigenic gut hormone, was markedly elevated and displayed an augmented response to feeding. 3) Acylated ghrelin, an orexigenic gut hormone, was lower and did not exhibit the premeal spike as observed in the controls. 4) neuropeptide Y (NPY), a potent orexigenic peptide, was markedly elevated and did not display any circadian variation. 5) Norepinephrine, marginally elevated, did not exhibit the normal nocturnal dip. By contrast, α-melanocyte-stimulating hormone and glucagon-like peptide-1 were not different between the two groups. Despite these hormonal abnormalities, HD patients maintained a good appetite and had normal body lean and fat mass, and there was no evidence of increased energy expenditure or protein catabolism. We explain the hormonal abnormalities as well as the absence of anorexia on suppression of parasympathetic activity (vagus nerve dysfunction), a phenomenon well documented in dialysis patients. Unexpectedly, we noted that the combination of high leptin, PYY, and NPY with suppressed ghrelin may increase arterial blood pressure, impair vasodilatation, and induce cardiac hypertrophy, and thus could predispose to adverse cardiovascular events that are the major causes of morbidity and mortality in the HD population. This is the first report attempting to link hormonal abnormalities associated with energy homeostasis to adverse cardiovascular outcome in the HD patients.

Topics: Adult; Anorexia; Appetite; Body Composition; Cardiovascular Diseases; Circadian Rhythm; Endocrine System Diseases; Energy Metabolism; Fasting; Female; Ghrelin; Homeostasis; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Peptide YY; Protein-Energy Malnutrition; Renal Dialysis; Renal Insufficiency; Risk Factors

The leucine7 to proline7 (Leu7Pro) polymorphism in preproneuropeptide Y (preproNPY) has been associated with accelerated atherosclerosis and type II diabetes, both of which are obesity-related diseases. The current study evaluated the impact of obesity on the disease risk linked to the Leu7Pro polymorphism of preproNPY in 393 elderly subjects. In 6 years follow-up, the polymorphism alone did not change the risk for abnormal glucose regulation, while obesity was associated with a significant 3-fold risk (odds ratio (OR) 2.95; 95% confidence interval (CI) 1.81-4.81, P<0.001) and the Leu7Pro polymorphism-obesity interaction, with a remarkable 12-fold risk (OR 12.33; 95% CI 1.18-128.35, P<0.05). The Leu7Pro polymorphism modified significantly the 10-year incidence of cardiovascular events, causing a 7.6-fold increase in the hazard ratio (HR 7.58; 95% CI 2.87-20.03, P<0.001) in the obese but not in the nonobese subjects. The results indicate that obesity may be a pivotal factor in multiplying the disease risk associated with the Leu7Pro polymorphism in preproNPY.

Topics: Aged; Blood Glucose; Blood Pressure; Body Mass Index; Body Weight; Cardiovascular Diseases; Diabetes Mellitus; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Male; Neuropeptide Y; Obesity; Polymorphism, Single Nucleotide; Risk Factors

To compare whether serum lipids and their changes during a health education intervention are associated with the Leu7Pro polymorphism in the signal peptide part of neuropeptide Y (NPY) in children with normal weight and in those with overweight.. An intervention study.. A family-based intervention of risk factors for prevention of CHD in Finland.. Subjects were 443 children with a family history of CVD participating in family-based health education. The children were divided into two groups according to NPY genotype: children with Leu7/Pro7 or Pro7/Pro7 genotype (n 50) and children with Leu7/Leu7 genotype (n 393). The final sample of the follow-up study included 353 (80 %) children (Pro7 allele carriers, n 43; Leu7/Leu7, n 310).. At baseline, the Leu7Pro polymorphism was not associated with serum lipid values after adjustment for body weight in boys or girls. There was a significant interaction of NPY genotype group by time and body weight (P = 0.043 for three-way interaction: time x NPY genotype x body weight) in LDL-cholesterol (LDL-C) concentration among boys. LDL-C decreased among boys with normal weight in both NPY groups and in overweight boys with the Leu7/Leu7 genotype, whereas it increased in overweight boys with the Pro7 allele. Two-way interaction (time x NPY genotype) showed no significant differences in changes of serum lipids between the NPY genotype groups among boys or girls.. The Leu7Pro polymorphism may be associated with dietary response to LDL-C concentration in overweight boys with a family history of early-onset CVD.

Topics: Adolescent; Adolescent Nutritional Physiological Phenomena; Alleles; Cardiovascular Diseases; Child; Child Nutritional Physiological Phenomena; Cholesterol, LDL; Female; Finland; Genetic Predisposition to Disease; Genotype; Health Education; Humans; Leucine; Lipids; Male; Neuropeptide Y; Overweight; Polymorphism, Genetic; Proline; Public Health; Risk Factors; Sex Factors; Thinness

Chronic renal insufficiency is a situation characterized by high plasma concentration of neuropeptide Y (NPY). Because this neuropeptide interferes with cardiovascular (CV) function, it is possible that it is involved in the high CV-related morbidity and mortality of these patients. To test this hypothesis, a follow-up study was performed (average duration, 34 mo; range 0.2 to 52.0 mo) in a cohort of 277 patients with end-stage renal disease receiving chronic dialysis. Univariate analysis revealed that plasma NPY was directly related to plasma norepinephrine (r = 0.37, P < 0.001) and epinephrine (r = 0.17, P = 0.005), exceeding the upper limit of the normal range in the majority of patients with end-stage renal disease (170 of 277, 61%). One hundred thirteen patients had one or more fatal and nonfatal CV events; 112 patients died, 66 of them (59%) of CV causes. Plasma NPY failed to predict all-cause mortality but was an independent predictor of adverse CV outcomes (hazard ratio [10 pmol/L increase in plasma NPY], 1.32; 95% confidence interval, 1.09 to 1.60; P = 0.004) in a Cox proportional-hazard model that included a series of traditional and nontraditional CV risk factors. Plasma NPY maintained its predictive power for CV events in statistical model including plasma norepinephrine. Plasma NPY predicts incident CV complications in end-stage renal disease. Controlled trials are needed to establish whether interference with the sympathetic system, NPY, or both may reduce the high CV morbidity and mortality of dialysis patients.

Topics: Adult; Aged; Biomarkers; Cardiovascular Diseases; Epinephrine; Female; Follow-Up Studies; Humans; Incidence; Kidney Failure, Chronic; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Predictive Value of Tests; Prospective Studies; Risk Factors; Survival Analysis; Urea; Uremia

Hyperplasia of vascular smooth muscle cells (VSMCs) occurs during HIV infection, part of a spectrum of HIV-mediated cardiovascular and microvascular pathologies. These changes are not due to direct viral infection but may involve the receptor-mediated action of viral proteins, such as the envelope protein gp120. We sought to identify gp120 receptors which might mediate the vascular smooth muscle cell hyperplasia present in HIV infection. A homology between neuropeptide Y (NPY) and the previously identified receptor-active V2-region of gp120 defined by an octapeptide sequence (Peptide T) related to VIP was noted. Since NPY is mitogenic for VSMCs we therefore determined whether gp120 shares this activity. Rat aortic VSMCs were treated for 24 h with human (h)NPY and gp120 in the presence of 0.5% serum to measure [3H]thymidine incorporation, an index of cell proliferation. NPY increased [3H]thymidine incorporation by 80% after a 24-h treatment in a bimodal fashion, with peak effects at 10(-10) M and 10(-8) M. Gp120 was an even more potent mitogen for VSMCs with peak activity occurring at 10(-12) M. Peptide T was equipotent with gp120, and slightly less efficacious, suggesting that this domain may mediate gp120 effects on VSMCs. When combined, gp120 and NPY acted to antagonize one another, lowering DNA synthesis to basal levels. The profile of pharmacologic inhibition supports a role for NPY receptors since antagonists of Y1 and Y2 subtypes substantially or completely inhibited gp120-mediated VSMC proliferation. This is the first demonstration of the proliferative effects of HIV viral protein gp120 on VSMCs. The effect appears to be mediated via gp120 sequences related to VIP, peptide T, and NPY. These ligands may be competitive inhibitors of binding or gp120 processing. Novel treatments may emerge based upon VIP and NPY receptor antagonists if further work substantiates a role for gp120 in the vascular abnormalities of AIDS.

Topics: Amino Acid Sequence; Animals; Cardiovascular Diseases; Cell Division; Cells, Cultured; HIV; HIV Envelope Protein gp120; HIV Infections; Humans; Hyperplasia; Mitogens; Molecular Sequence Data; Muscle, Smooth, Vascular; Neuropeptide Y; Peptide T; Rats; Receptors, Neuropeptide Y; Sequence Homology, Amino Acid; Vasoactive Intestinal Peptide

Some evidences indicate that the female sex hormones protect against the development of cardiovascular diseases. Modulation of sympathetic activity may be one of the possibilities. We investigated the influence of treadmill stress on blood pressure (BP) and plasma neuropeptide Y (NPY), norepinephrine (NE) and epinephrine (E) concentrations in 11 normotensive, menstruating women in the follicular (HWf) and luteal (HWl) phases and in eight ovariectomized women, before (OVX) and after estrogen supplementation (OVXe). Both at rest and during exercise there were no differences in BP between HWf and HWl and between OVX and OVXe. During stress BP was significantly lower in HWf and HWl than in OVX but not in OVXe. NPY did not differ significantly between the groups of women either at rest or during activity. We did not observe differences in resting and stimulated NE and E between HWf and HWl and between OVX and OVXe. Neither resting nor activated NE and E differed between the groups, except higher stimulated NE in OVX than in HWf. These results suggest that the female sex hormones may modulate the BP response to dynamic exercise. Our data support evidence that this influence may be exerted by circulating catecholamines and not by NPY.

Topics: Adult; Blood Pressure; Cardiovascular Diseases; Epinephrine; Estrogen Replacement Therapy; Exercise; Female; Gonadal Steroid Hormones; Humans; Menstrual Cycle; Neuropeptide Y; Norepinephrine; Ovariectomy; Stress, Physiological