neuropeptide-y and Carotid-Artery-Diseases

We investigated the associations of inflammatory blood cell activation with vascular parameters in patients with type 2 diabetes to elucidate the possible mechanisms of accelerated atherosclerosis observed in subjects with the Leucine 7 to Proline 7 polymorphism (Leu7Pro) in the neuropeptide Y (NPY).. Our study included 31 Caucasian patients with type 2 diabetes; 12 of them had the Leu7Pro7 (heterozygous), and 19 had the Leu7Leu7 (wild type) genotype. Vascular parameters were determined by ultrasound methods. Leukocyte analyses were performed from blood samples using flow cytometry. NPY concentrations were determined in plasma.. The amount of platelet-granulocyte complexes was positively correlated with NPY concentration (p=0.008) and carotid intima-media thickness (p=0.035) in the Leu7Pro7 group. Interferon gamma (IFN-γ) expression in monocytes correlated negatively with brachial artery flow-mediated dilatation also in the Leu7Pro7 group (p=0.037). The expression of tissue factor on monocytes correlated negatively with brachial artery diameter in the Leu7Pro7 patients as well (p=0.019).. The results indicate significant associations between inflammatory cell activation in blood and vascular atherosclerosis in genetically prone subjects, and provide possible mechanistic information about the role of NPY and the Leu7Pro polymorphism in the development of atherosclerosis.

Topics: Aged; Analysis of Variance; Brachial Artery; Carotid Artery Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Finland; Flow Cytometry; Genotype; Humans; Inflammation; Interferon-gamma; Leukocytes; Linear Models; Male; Middle Aged; Neuropeptide Y; Phenotype; Proline; Risk Assessment; Risk Factors; Ultrasonography; Vasodilation

We reported previously that neuropeptide Y (NPY) induces an atherosclerotic-like lesion that is significantly reduced by NPY-Y1 and NPY-Y5 receptor (R) inhibitors. Because antagonists also inhibit neointima induced by angioplasty alone, we now test whether stress-induced endogenous NPY release mimic these changes.. Rats were nonstressed or stressed (4 degrees C water; 2 hours per day for 14 days) starting immediately before and continuing after carotid artery angioplasty. Stress acutely and chronically increased blood pressure and doubled plasma NPY levels. After 14 days, angioplasty-induced neointima was markedly greater in stressed (than nonstressed) rats, in which most of the vessels became occluded with an atherosclerotic-like lesion containing macrophages, lipids, thrombus, and microvessels that was similar but more inflammatory than the injury in the NPY-treated vessels. Fourteen days after angioplasty combined with stress or NPY, Y1R and Y5R (mRNA and protein) became upregulated in areas of neointima, microvessels, and macrophages in injured carotid arteries. Stress- and NPY-induced changes were completely prevented by a selective Y1R antagonist (0.02 micromol/kg per minute for 14 days), whereas neointima induced by angioplasty alone was reduced by 60%.. Because of sympathetic NPY release, stress may be a less-than-appreciated risk factor for restenosis/atherosclerosis, and Y1R antagonists a potential therapy for these conditions.

Topics: Angioplasty, Balloon; Animals; Blood Pressure; Carotid Artery Diseases; Carotid Artery Injuries; Carotid Stenosis; Chronic Disease; Cold Temperature; Male; Neuropeptide Y; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Recurrence; Risk Factors; RNA, Messenger; Stress, Physiological; Sympathetic Nervous System; Tunica Intima; Tunica Media

A rather common leucine7-to-proline7 (Leu7Pro) polymorphism in the preproneuropeptide Y (prepro-NPY) gene signal peptide may be important in blood pressure regulation, cholesterol metabolism and the pathogenesis of atherosclerosis in humans. We examined the associations of the Leu7Pro polymorphism with carotid atherosclerotic progression, blood pressure and serum lipids in a population-based sample of 966 men aged 42-60 years in Finland. The Pro7 substitution (carrier frequency 12.2%) was associated with accelerated four-year increase in the mean (P=0.01) and maximal (P=0.007) common carotid intima-media thickness (IMT) and with slightly increased systolic (P=0.03) and diastolic (P=0.02) blood pressures, adjusted for other major risk factors. Men with Pro7 substitution had 30.6% (95% CI 6.9-54.0%) greater increase in the mean IMT and 20.0% (95% CI 5.3-34.4%) greater increase in the maximal IMT than men with Leu7/Leu7 genotype. The Pro7 substitution was also related to increased serum total cholesterol (P=0.01) and LDL cholesterol (P=0.02) in obese (body mass index (BMI)>30 kg/m(2)) men. This study provides important evidence suggesting that the Pro7 substitution in the prepro-NPY is an important risk factor for accelerated atherosclerotic progression, increased blood pressure and increased serum cholesterol in humans.

Topics: Adult; Blood Pressure; Carotid Artery Diseases; Disease Progression; Finland; Humans; Leucine; Lipids; Male; Middle Aged; Neuropeptide Y; Polymorphism, Genetic; Proline; Protein Precursors; Risk Factors

Nerve fibers, immunohistochemically positive for neuropeptide Y, tyrosine hydroxylase, calcitonin gene-related peptide and substance P, form a perivascular network surrounding the carotid arteries of New Zealand White rabbits. Transmission electron microscopy demonstrates that the nerve fibers are primarily located at the adventitial-medial border. Placing a silastic collar around a carotid artery for 14 days, in rabbits fed a diet high in cholesterol, resulted in a focal, intimal thickening in 10 out of 12 rabbits. Contralateral sham-operated arteries showed no intimal thickening. At sites where intimal thickening occurred, there was a disappearance of the perivascular nerve network. The carotid arteries from rabbits that did not respond to the collar and the sham-operated carotid arteries showed an intact and normal perivascular nerve network. In the group of animals which responded to the collar with intimal thickening, there was evidence of a proliferative response proximal to the collar and in this same tissue there was evidence of degeneration of nerve fibers. In conclusion, it has been demonstrated for the first time that, in regions of the carotid artery where intimal thickening occurred, there was an associated degeneration of the perivascular nerve network. The cause of this degeneration and its functional consequences require further investigation.

Topics: Animals; Calcitonin Gene-Related Peptide; Carotid Arteries; Carotid Artery Diseases; Immunoenzyme Techniques; Intracranial Arteriosclerosis; Male; Microscopy, Electron; Muscle, Smooth, Vascular; Nerve Fibers; Nerve Net; Neuropeptide Y; Rabbits; Substance P; Tyrosine 3-Monooxygenase