neuropeptide-y and Hypercholesterolemia

Beyond their hypolipidemic effect, statins reduce cardiovascular risk in hypertensive subjects via various mechanisms; one suggested mechanism is that they reduce sympathetic activity. We investigated the hypothesis that simvastatin decreased muscle sympathetic nerve activity (MSNA) in 31 hypertensive subjects with hypercholesterolemia (aged 38.7 ± 10 years). In this randomized, placebo-controlled, double-blinded study, patients were treated with simvastatin (40 mg day(-1); n=15) or placebo (n=16) for 8 weeks. Before and after treatment, we measured MSNA, blood pressure and heart rate. Baroreceptor control of the heart rate, or baroreceptor sensitivity (BRS), was computed by the sequence method, a cross-analysis of systolic blood pressure and the electrocardiogram R-R interval. Blood samples were tested for plasma levels of catecholamines, neuropeptide Y, aldosterone, endothelin and renin activity. Simvastatin significantly reduced MSNA (from 36.5 ± 5 to 27.8 ± 6 bursts per min, P=0.001), heart rate (from 77 ± 6.7 to 71 ± 6.1 beats per min, P=0.01) and both total and low-density lipoprotein cholesterol (from 249 ± 30.6 to 184 ± 28.3 mg dl(-1), P=0.001 and from 169 ± 30.6 to 117 ± 31.2 mg dl(-1), P=0.01, respectively). Simvastatin also improved BRS (from 10.3 ± 4.1 to 17.1 ± 4.3 ms per mm Hg, P=0.04). No changes were observed in systolic or diastolic blood pressures, or in plasma levels of catecholamines, neuropeptide Y, endothelin, aldosterone and renin activity. After simvastatin therapy, MSNA and BRS were inversely related (r=-0.94, P<0.05). In conclusion, we found that, in patients with hypertension and hypercholesterolemia, simvastatin reduced MSNA, and this was related to increased baroreceptor sensitivity.

Topics: Adult; Aldosterone; Anticholesteremic Agents; Blood Pressure; Catecholamines; Comorbidity; Double-Blind Method; Endothelins; Heart Rate; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Neuropeptide Y; Pressoreceptors; Renin; Simvastatin; Sympathetic Nervous System; Treatment Outcome

A gain-of-function polymorphism in human neuropeptide Y (

Topics: Adrenergic Neurons; Animals; Cholesterol; Diabetes Mellitus, Type 2; Energy Intake; Energy Metabolism; Fatty Acids; Fatty Liver; Gene Expression; Glucose; Hypercholesterolemia; Liver; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuropeptide Y; Obesity; Receptors, Neuropeptide Y; Sympathetic Nervous System

While the angiogenic effects of Neuropeptide Y (NPY) in myocardial ischemia and hypercholesterolemia have been studied, its effects on altering oxidative stress, fibrosis and cell death are not known. We hypothesized that local infiltration of NPY in a swine model of chronic myocardial ischemia and hypercholesterolemia will induce nerve growth and cell survival, while reducing oxidative stress and fibrosis. Yorkshire mini-swine (n=15) were fed a high cholesterol diet for 5 weeks. Three weeks after surgical induction of focal myocardial ischemia, an osmotic pump was implanted, which delivered NPY (n=8, high cholesterol treated, HCT) or the vehicle (n=7, high cholesterol control, HCC) for 5 weeks. Then myocardium was harvested for analysis. Assessment of myocardial function and perfusion was made the last intervention. Immunoblotting demonstrated significantly decreased levels of MMP-9 (p=0.001) and TGF-β (p=0.05) and significantly increased levels of Ang-1 (p=0.002), MnSOD (p=0.006) and NGF (p=0.01) in HCT. Immunohistochemistry results revealed significantly decreased TUNEL staining (p=0.005) and GLUT4 translocation (p=0.004) in HCT. The functional data showed significantly improved blood flow reserve (p=0.02) and improved diastolic function -dP/dt (p=0.009) in the treated animals. Local infiltration of NPY results in positive remodeling in ischemic myocardium in the setting of hypercholesterolemia. By initiating angio and neurogenesis, NPY infiltration improves blood flow reserve and restoration of fatty acid metabolism. The associated increased cell survival and decreased fibrosis result in improved myocardial diastolic function. NPY may have a potential therapeutic role in patients with hypercholesterolemia associated coronary artery disease.

Topics: Animals; Apoptosis; Cell Membrane; Cell Proliferation; Cell Survival; Chronic Disease; Coronary Angiography; Disease Models, Animal; Fatty Acids; Fibrosis; Gene Expression Regulation; Glucose Transporter Type 4; Heart Ventricles; Hypercholesterolemia; Hypertrophy; Male; Myocardial Ischemia; Myocytes, Cardiac; Neovascularization, Pathologic; Neuropeptide Y; Oxidative Stress; Swine

Pharmacologically induced angiogenesis could be a promising option in clinical situations with diffuse inoperable coronary artery disease e.g. metabolic syndrome and diabetes mellitus. The failure of focused cytokine, stem cell and gene therapies to achieve both perfusion and functional improvement in clinical trials suggests a more centralized control mechanism. Neuropeptide-Y (NPY) is one such natural neurotransmitter that is known to exert a multifaceted role during neo-angiogenesis and can possibly act as the central control. To date, the ability to harness the 'master switch' nature of NPY in a specific experimental model of metabolic syndrome and chronic myocardial ischemia has not been conclusively demonstrated. We hypothesized that infiltration of NPY into an area of chronic ischemia in a metabolic syndrome swine model would induce angiogenesis and improve myocardial perfusion and function. An osmotic pump was inserted three weeks after surgical induction of focal myocardial ischemia. We delivered either NPY or placebo for five weeks, after which the myocardial tissue was harvested for analysis. Assessments of myocardial perfusion and function were performed at each stage of the experiment. Local infiltration of NPY significantly improved collateral vessel formation, blood flow and myocardial function. We believe activation of NPY receptors may be a potential target therapy for patients with diffuse coronary artery disease.

Topics: Angiogenesis Inducing Agents; Animals; Coronary Angiography; Coronary Circulation; Disease Models, Animal; Hypercholesterolemia; Male; Myocardial Ischemia; Myocardium; Neuropeptide Y; Receptors, Neuropeptide Y; Swine

Acetyl-coenzyme A carboxylase alpha (ACACA) single-nucleotide polymorphism (SNP) (rs2229416) was significantly associated with hypertriglyceridemia, during exploration of antipsychotic direct effects on lipids. Neuropeptide Y (NPY) gene (rs1468271) and ACACB gene (rs2241220) SNPs were significantly associated with severe hypercholesterolemia. In the same sample (173 patients on olanzapine, quetiapine, chlorpromazine or mirtazapine [increasing the risk of hyperlipidemia] and 184 controls taking other antipsychotics), three (rs1266175, rs12453407 and rs9906543) of eight additional ACACA SNPs were significantly associated with hypertriglyceridemia in those taking drugs of interest, but not in controls. Five other ACACA SNPs, three additional NPY SNPs, and seven additional ACACB SNPs were not significant.

Topics: Acetyl-CoA Carboxylase; Adult; Antipsychotic Agents; Cholesterol; Cross-Sectional Studies; Female; Humans; Hypercholesterolemia; Logistic Models; Male; Middle Aged; Neuropeptide Y; Pharmacogenetics; Polymorphism, Single Nucleotide; Psychotic Disorders; Sequence Analysis, DNA; Triglycerides

Orlistat is an inhibitor of lipase which splits triglycerides into free fatty acides and glycerol. This drug, by inhibiting hydrolysis of triglycerides, is the cause of significant loss of fat in the faeces. 13 obese and 15 nonobese subjects were examined. Obese subjects received orlistat (Xenical, F. Hoffmann La Roche Ltd, Switzerland) 3 x 120 mg/d. Treatment with orlistat for 16 weeks was followed by a significant fall of BMI and MAP, insulinemia, insulin/glucose ratio, leptinemia, serum total cholesterol, triglycerides, HDL-cholesterol and 25-OH-D concentration respectively. Orlistat did not influence significantly serum LDL-cholesterol concentration but unexpectedly increased plasma levels of folic acid, vitamin B12 and NPY.. (1) Monitoring of plasma 25-OH-D levels in obese patients on orlistat therapy seems to be mandatory. (2) In spite of significant changes (in opposite direction) in leptinemia and serum NPY level observed in obese subjects treated with orlistat, presence of a functional relationship between these hormones could not be confirmed.

Topics: Adult; Anti-Obesity Agents; Blood Glucose; Carbohydrates; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Enzyme Inhibitors; Female; Hormones; Humans; Hypercholesterolemia; Hyperlipidemias; Insulin; Lactones; Leptin; Lipase; Lipids; Male; Neuropeptide Y; Obesity; Orlistat; Poland; Time Factors; Treatment Outcome; Triglycerides; Vitamins; Weight Loss

Neuropeptide Y (NPY) is a molecule that may have both vasoconstrictive and vasodilatory actions. A common polymorphism in the human NPY gene that results in the Leucine7 to Proline7 substitution (Leu7Pro) in the signal peptide part of the NPY was recently identified. This substitution has been associated with elevated serum cholesterol levels and with slightly accelerated progression rate of carotid intima-media thickness, thus suggesting increased risk of atherosclerosis in carriers of Pro7 substitution. Recent data also indicate that subjects with Pro7 substitution may have increased endothelial release of NPY. This study was undertaken to elucidate the effects of Leu7Pro polymorphism on arterial endothelial function. We measured flow-mediated endothelial-dependent dilatation (FMD) of the brachial artery in two separate populations: in 152 middle-aged men and in 95 prepubertal children. In both study populations, subjects with Pro7 substitution had 48-52% higher FMD compared with subjects having the wildtype (Leu7/Leu7) signal peptide sequence. We conclude that Pro7 substitution in signal peptide of the NPY is associated with enhanced endothelial-dependent vasodilation. Prospective studies are needed to determine whether Pro7 substitution is associated with increased or decreased risk of cardiovascular morbidity and mortality.

Topics: Adult; Age Factors; Aged; Analysis of Variance; Blood Pressure Determination; Brachial Artery; Child; Coronary Disease; Endothelium, Vascular; Female; Genetic Predisposition to Disease; Humans; Hypercholesterolemia; Leucine; Male; Middle Aged; Neuropeptide Y; Polymorphism, Genetic; Probability; Proline; Prospective Studies; Protein Sorting Signals; Reference Values; Risk Factors; Sampling Studies; Statistics, Nonparametric; Vasodilation

Neuropeptide Y (NPY) is a 36 amino acid peptide well known for its role in regulating food intake and energy homeostasis. It has previously been shown that the NPY Y2 receptor is required for a full biological response to leptin in the central nervous system. We have examined the impact of this receptor on plasma levels of lipid and cholesterol in wild type and obese (ob/ob) mice. The results show that an absence of Y2 in female mice has no effect on cholesterol level in normal lean mice but profoundly decreases serum cholesterol and glucose levels in ob/ob mice. We conclude that NPY, interacting with the Y2 receptor, participates in cholesterol and glucose homeostasis of obese mice.

Topics: Animals; Blood Glucose; Body Weight; Cholesterol; Crosses, Genetic; Female; Hypercholesterolemia; Hyperglycemia; Leptin; Lipids; Lipoproteins; Mice; Mice, Inbred BALB C; Mice, Obese; Mice, Transgenic; Neuropeptide Y; Receptors, Neuropeptide Y; Temperature; Time Factors

Topics: Adipose Tissue; Arteriosclerosis; Cholesterol; Diet; Humans; Hypercholesterolemia; Neuropeptide Y; Obesity; Polymorphism, Genetic