neuropeptide-y and Arteriosclerosis

Attempts to restore blood flow through atherosclerotic vessels by angioplasty often result in restenosis. Because the role of nerves in this process is unclear, we investigated whether neuropeptide Y (NPY), a sympathetic cotransmitter with vascular mitogenic activities, contributes to postangioplasty restenosis.. Carotid artery balloon angioplasty upregulated vascular expression of NPY and its processing enzyme (DPPIV/cd26) and receptors (Y1, Y2, Y5 mRNA and protein) within 6 to 24 hours and stimulated neointima formation and accumulation of NPY in platelets after 14 days. NPY pellets (1 to 10 microg/pellet for 14 days) inserted next to the injured artery elevated platelet and vascular NPY immunoreactivity to stress-like levels and dose-dependently augmented angioplasty-induced neointima. Strikingly, 10 microg NPY for 14 days led to vessel occlusion with an atherosclerotic-like lesion, with thrombus and neointima containing neovessels, macrophages, matrix, and lipids. Y1 or Y5 receptor antagonist completely prevented the effect of NPY and reduced angioplasty-induced neointima by 50%.. Angioplasty upregulates platelet and vascular NPY systems, which then contribute to neointima formation via Y1 and Y5 receptor activation. Increasing NPY to high stress levels triggers formation of a thrombotic atherosclerotic-like lesion and vessel occlusion. Thus, NPY may be a risk factor for accelerated atherosclerosis, and NPY receptor antagonists may be a possible new treatment for restenosis.

Topics: Analysis of Variance; Angioplasty, Balloon; Animals; Arteriosclerosis; Blood Platelets; Carotid Artery, Common; Carotid Stenosis; Endothelium, Vascular; Male; Neuropeptide Y; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Recurrence; Tunica Intima; Up-Regulation

Topics: Angioplasty, Balloon, Coronary; Animals; Arteriosclerosis; Endothelial Cells; Endothelium, Vascular; Neuropeptide Y; Rats; Receptors, Neuropeptide Y; Tunica Intima

We have recently demonstrated that subjects having Pro7 in the signal peptide ofneuropeptide Y (NPY) have higher serum cholesterol and apolipoprotein B levels than individuals with wild-type (Leu7Leu7) signal peptide sequence. We investigated the association of Leu7Pro polymorphism with common carotid intima media thickness (IMT) assessed by ultrasonograph in patients with type 2 diabetes (n = 81; 41 men and 40 women; mean age, 67.1 yr) and nondiabetic subjects (n = 105; 48 men and 57 women; mean age, 65.5 yr) and genotyped for the Leu7Pro polymorphism in prepro-NPY. The frequency of Pro7 in prepro-NPY was 9.9% (8 of 81) in diabetic patients and 14.3% (15 of 105) in control subjects (P = 0.360). The mean common carotid IMT was 1.04 +/- 0.02 mm in nondiabetic subjects without the Leu7Pro polymorphism and 1.14 +/- 0.04 mm in nondiabetic subjects with in (P = 0.156) and 1:18 +/- 0.03 and 1.58 +/- 0.21mm in diabetic patients without and with the Leu7Pro polymorphism (P = 0.004), respectively. In the analysis of covariance of the entire group, the mean common carotid IMT was independently associated with the Leu7Pro polymorphism (F = 5.165; P = 0.024) after adjustment for known risk factors. Thus, the presence of the Pro7 substitution in the prepro-NPY associates with increased carotid atherosclerosis.

Topics: Aged; Amino Acid Substitution; Arteriosclerosis; Autonomic Nervous System; Blood Pressure; Carotid Stenosis; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Genotype; Heart Rate; Humans; Leucine; Male; Neuropeptide Y; Polymorphism, Genetic; Proline; Risk Factors

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

High serum total and low-density lipoprotein (LDL) cholesterol levels constitute the main risk factor for atherosclerotic vascular diseases. Both genetic and environmental factors are involved in the regulation of serum cholesterol levels. Neuropeptide Y (NPY), which is widely expressed in both the central and peripheral nervous systems, is known to regulate food intake and energy balance but its role in cholesterol metabolism has remained almost untouched in former literature. A newly discovered association between a leucine(7)-to-proline(7) polymorphism (Pro(7)) in the signal peptide of NPY and a high cholesterol level may provide new ideas for the genetic regulation of cholesterol metabolism. The presence of the Pro(7) in NPY results in serum total cholesterol levels 0.6-1.4 mmol/L higher compared with subjects without this gene variant. The Pro(7) in NPY was detected in 14% of Finns but only in 6% of Dutchmen, and its impact on serum cholesterol concentration seems to be stronger in obese than in normal-weight subjects. At least among Finns, the Pro(7) in NPY is one of the strongest genetic factors identified thus far affecting serum cholesterol levels.

Topics: Arteriosclerosis; Cholesterol; Female; Humans; Male; Neuropeptide Y; Neurosecretory Systems; Obesity; Risk Factors

We used the fluorescent Ca2+ indicator Fura-2 in cultured porcine aortic smooth muscle cells (PASMC) to study effects of the sympathetic neurotransmitters norepinephrine (NE) and neuropeptide Y (NPY) on free intracellular Ca2+ (Cai). Both transmitters transiently increased intracellular Ca2+ in a concentration-dependent manner. Selective agonists and antagonists demonstrated that the NE-stimulated Cai increase is predominantly (if not exclusively) mediated by alpha 2-adrenoceptors, whereas the NPY response appears to be mediated by the peptide YY-insensitive Y3-like receptor subtype. Pretreatment of cells with pertussis toxin abolished NPY and alpha-adrenoceptor agonist-stimulated intracellular Ca2+ elevations (but not those stimulated by angiotensin II) suggesting involvement of a Gi-like G-protein. alpha 2-Adrenoceptor-stimulated Ca2+ increases resulted from mobilization from intracellular stores, whereas Y3-like NPY receptors mobilized Ca2+ from intracellular stores and also promoted Ca2+ influx.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Aorta; Arteriosclerosis; Calcium; Cells, Cultured; Disease Models, Animal; GTP-Binding Proteins; Muscle, Smooth, Vascular; Neuropeptide Y; Norepinephrine; Swine

The neuromodulatory actions of neuropeptide Y (NPY) (0.1 microM) and calcitonin gene-related peptide (CGRP) (0.01 microM) on nerve-evoked contractions have been studied in the Watanabe heritable hyperlipidemic (WHHL) rabbit mesenteric artery from 4-, 6- and 12-month-old animals with New Zealand white (NZW) rabbits being used as age- and sex-matched controls. Nerve-evoked contractions in 12-month-old rabbits were smaller in WHHL in comparison to NZW rabbits, with no difference between the two strains of rabbit at 4 and 6 months of age. Both the potentiating effect of NPY and the inhibitory effect of CGRP on nerve-evoked contractions increased significantly at 12 months of age compared with responses measured in younger WHHL rabbits, and were greater than in 12-month-old control NZW rabbits. In contrast, the direct smooth muscle relaxant response of CGRP on raised-tone preparations was not different between the two strains of rabbit at any age. Both NPY-immunoreactive and CGRP-immunoreactive nerve fibres were less varicose in 6- and 12-month-old WHHL rabbits when compared with younger WHHL rabbits and NZW controls. In conclusion, this study shows that while nerve-evoked contractions are reduced, in the 12-month-old WHHL rabbit mesenteric artery, the neuromodulatory actions of NPY and CGRP are augmented.

Topics: Age Factors; Animals; Arteriosclerosis; Calcitonin Gene-Related Peptide; Female; Mesenteric Arteries; Microscopy, Fluorescence; Nerve Fibers; Neuropeptide Y; Rabbits; Sympathetic Nervous System; Synaptic Transmission