Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effects of neuropeptide Y on the prostacyclin production of cultured porcine aortic endothelial cells by measuring the stable metabolite of prostacyclin, 6-keto-prostaglandin F1 alpha, by radioimmunoassay. Neuropeptide Y induced dose- and time-dependent stimulation of prostacyclin production by cultured porcine aortic endothelial cells. The lowest stimulatory concentration of neuropeptide Y was 10(-8) M and maximal response, a 2.8 fold rise, was obtained with 10(-6) M. The stimulation lasted at least 24 h. The effect was associated with the stimulation of arachidonic acid release. Our data suggest that neuropeptide Y may inhibit the development of atherosclerosis by stimulating prostacyclin synthesis.
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PMID:Neuropeptide Y stimulates prostacyclin production in porcine vascular endothelial cells. 188 60

This investigation involved alterations in the local control of vascular tone in the isolated rabbit basilar artery in atherosclerosis, with Watanabe heritable hyperlipidemic (WHHL) rabbits as a model and New Zealand White (NZW) rabbits as controls. Vasoconstrictor responses to KCl in isolated preparations of the basilar artery at basal tone showed no differences at 4, 6, and 12 months of age in either WHHL or NZW rabbits. Contractile responses to both histamine and neuropeptide Y were significantly greater in 12-month-old WHHL rabbit preparations when compared with responses measured at 4 and 6 months. In NZW rabbit preparations, there was no change in maximum contractile responses to both histamine and neuropeptide Y over the same age range. Endothelium-dependent relaxations to acetylcholine in raised-tone preparations from WHHL rabbits were significantly greater at 6 months in comparison with responses measured at both 4 and 12 months of age. In contrast, endothelium-independent relaxations to calcitonin gene-related peptide and vasoactive intestinal polypeptide showed no change over the age range studied. In NZW rabbit preparations, both endothelium-dependent and endothelium-independent relaxations declined significantly between 4 and 12 months. The significance of these changes in the rabbit basilar artery in atherosclerosis is discussed in relation to the "protection" of intracranial arteries from atherosclerosis and their subsequent susceptibility to cerebral ischemia and stroke.
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PMID:Changes in vasoconstrictor and vasodilator responses of the basilar artery during maturation in the Watanabe heritable hyperlipidemic rabbit differ from those in the New Zealand White rabbit. 191 1

In the submitted review the author deals with specific features of the coronary circulation, coronary reserve and importance of regulation of the tonus of the coronary arteries at their epicardiac course and the tonus at the arteriolar level. In the subsequent part the author deals systematically first with the nervous regulation incl. the basic importance of the alpha-adrenergic (vasoconstrictor) and beta-adrenergic (vaso-dilating) sympathomimetic component. He mentions also the importance of neuropeptides (neuropeptide Y and substance P). Attention is devoted to the importance of the endothelium and endothelial vasoactive substances in the control of circulation. The main representatives of substances with a vasodilatating action are the endothelial relaxation factor and prostacycline, as to vasoconstrictor substances it is endothelin, thromboxan A2 and some growth factors. The authors discuss also the mechanical component, i. e. the influence of the blood flow and viscosity on the tonus of the coronary arteries. Finally the author draws attention to the clinical importance of disorders of regulatory mechanism in atherosclerosis and some clinical entities.
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PMID:[Regulation of coronary circulation]. 225 78

1. Extracellular adenosine triphosphate (ATP) is mitogenic for vascular smooth muscle cells (VSMC) and stimulates several events that are important for cell proliferation: DNA synthesis, protein synthesis, increase of cell number, immediate early genes, cell-cycle progression, and tyrosine phosphorylation. 2. Receptor characterization indicates mitogenic effects of both P2U and P2Y receptors. The P2X receptor is lost in cultured VSMC and is not involved. Several related biological substances such as UTP, ITP, GTP, AP4A, ADP, and UDP are also mitogenic. 3. Signal transduction is mediated via Gq-proteins, phospholipase C beta, phospholipase D, diacyl glycerol, protein kinase C alpha, delta, Raf-1, MEK, and MAPK. 4. ATP acts synergistically with polypeptide growth factors (PDGF, bFGF, IGF-1, EGF, insulin) and growth factors acting via G-protein-coupled receptors (noradrenaline, neuropeptide Y, 5-hydroxytryptamine, angiotensin II, endothelin-1). 5. The mitogenic effects have been demonstrated in rat, porcine, and bovine VSMC and cells from human coronary arteries, aorta, and subcutaneous arteries and veins. 6. The trophic effects on VSMC and the abundant sources for extracellular ATP in the vessel wall make a pathophysiological role probable in the development of atherosclerosis, neointima-formation after angioplasty, and possibly hypertension.
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PMID:Extracellular ATP: a growth factor for vascular smooth muscle cells. 959 70

The prevalence of obesity is rising at an alarming rate worldwide, with consequent increases in type 2 diabetes, hypertension and cardiovascular morbidity and mortality. Central neural mechanisms, via the activation of the sympathetic nervous system may contribute to obesity-related cardiovascular diseases through the promotion of hypertension, dysrhythmia and atherosclerosis. However, the mechanisms responsible for this sympatho activation have not been identified. Leptin is an adipocyte-derived hormone that promotes weight loss by reducing appetite and by increasing energy expenditure through sympathetic stimulation to thermogenic tissue. Leptin also produces sympathoactivation to kidneys, hindlimb and adrenal glands, suggesting that the obesity-associated increase in sympathetic nerve activity could be due in part to these sympathetic effects of leptin. However, most human obesity appears to be associated with leptin resistance. Recent studies indicate that leptin resistance may be selective, with preservation of adverse sympathetic effects despite the loss of the metabolic actions of leptin. The leptin receptor is expressed in several hypothalamic nuclei including the arcuate nucleus. The melanocortin system, neuropeptide Y and corticotrophin-releasing factor have emerged as principal neuropeptide mediators of leptin action in the arcuate nucleus. These neuropeptides exert varying effects by different pathways. Several other candidate hypothalamic pathways that can mediate the effects of leptin have been identified. The understanding of neuronal signaling pathways involved in leptin signaling and energy balance has opened new research possibilities for the treatment of obesity.
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PMID:Leptin and the central neural mechanisms of obesity hypertension. 1258 70

Rapid progress in human genome decoding has accelerated search for the role of gene polymorphisms in the pathogenesis of complex multifactorial diseases. This review summarizes the results of recent studies on the associations of common gene variants with multifactorial chronic conditions strongly affected by nutritional factors. Three main individual sections discuss genes related to energy homeostasis regulation and obesity, cardiovascular disease (CVD), and cancer. It is evident that several major chronic diseases are closely related (often through obesity) to deregulation of energy homeostasis. Multiple polymorphic genes encoding central and peripheral determinants of energy intake and expenditure have been revealed over the past decade. Food intake control may be affected by polymorphisms in the genes encoding taste receptors and a number of peripheral signaling peptides such as insulin, leptin, ghrelin, cholecystokinin, and corresponding receptors. Polymorphic central regulators of energy intake include hypothalamic neuropeptide Y, agouti-related protein, melanocortin pathway factors, CART (cocaine- and amphetamine-regulated transcript), some other neuropeptides, and receptors for these molecules. Potentially important polymorphisms in the genes encoding energy expenditure modulators (alpha- and beta- adrenoceptors, uncoupling proteins, and regulators of adipocyte growth and differentiation) are also discussed. CVD-related gene polymorphisms comprising those involved in the pathogenesis of atherosclerosis, blood pressure regulation, hemostasis control, and homocysteine metabolism are considered in a separate section with emphasis on multiple polymorphisms affecting lipid transport and metabolism and their interactions with diet. Cancer-associated polymorphisms are discussed for groups of genes encoding enzymes of xenobiotic metabolism, DNA repair enzymes, factors involved in the cell cycle control, hormonal regulation-associated proteins, enzymes related to DNA methylation through folate metabolism, and angiogenesis-related factors. There is an apparent progress in the field with hundreds of new gene polymorphisms discovered and characterized, however firm evidence consistently linking them with pathogenesis of complex chronic diseases is still limited. Ways of improving the efficiency of candidate gene approach-based studies are discussed in a short separate section. Successful unraveling of interaction between dietary factors, polymorphisms, and pathogenesis of several multifactorial diseases is exemplified by studies of folate metabolism in relation to CVD and cancer. It appears that several new directions emerge as targets of research on the role of genetic variation in relation to diet and complex chronic diseases. Regulation of energy homeostasis is a fundamental problem insufficiently investigated in this context so far. Impacts of genetic variation on systems controlling angiogenesis, inflammatory reactions, and cell growth and differentiation (comprising regulation of the cell cycle, DNA repair, and DNA methylation) are also largely unknown and need thorough analysis. These goals can be achieved by complex simultaneous analysis of multiple polymorphic genes controlling carefully defined and selected elements of relevant metabolic and regulatory pathways in meticulously designed large-scale studies.
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PMID:Common gene polymorphisms and nutrition: emerging links with pathogenesis of multifactorial chronic diseases (review). 1294 74

The various mechanisms that may explain the association between brain dysfunction and the pathogenesis of metabolic syndrome (MS) leading to cardiovascular disease and type 2 diabetes have been reviewed. A Medline search was conducted until September 2003, and articles published in various national and international journals were reviewed. Experts working in the field were also consulted. Compelling evidence was found that saturated and total fat and low dietary n-3 fatty acids and other long-chain polyunsaturated fatty acids (PUFAs) in conjunction with sedentary behavior and mental stress combined with various personality traits can enhance sympathetic activity and increase the secretion of catecholamine, cortisol and serotonin, all of which appear to be underlying mechanisms involved in MS. Excess secretion of these neurotransmitters in conjunction with underlying long-chain PUFA deficiency may damage the neurons in the ventromedial hypothalamus and insulin receptors in the brain, in particular during fetal life, infancy and childhood, and lead to their dysfunction. Since 30-50% of the fatty acids in the brain are long-chain PUFAs, especially omega-3 fatty acids which are incorporated in the cell membrane phospholipids, it is possible that their supplementation may have a protective effect. Omega-3 fatty acids are also known to enhance parasympathetic activity and to increase the secretion of anti-inflammatory cytokines as well as acetylecholine in the hippocampus. It is possible that a marginal deficiency of long-chain PUFAs, especially n-3 fatty acids, due to poor dietary intake during the critical period of brain growth and development in the fetus, and later in the infant and also possibly in the child, adolescent and adult may enhance the release of tumor necrosis factor-alpha (TNF-alpha) interleukin (IL)-1, 2 and 6 and cause neuronal dysfunction. Experimental studies indicate that ventromedial hypothalamic lesions in rats induce hyperphagia, resulting in glucose intolerance and insulin resistance. Treatment with neuropeptide Y abolished hyperphagia and ob mRNA (leptin mRNA) in this animal model. Long-term infusion of norepinephrine and serotonin into the ventromedial hypothalamus impaired pancreatic islet function inasmuch as ventromedial hypothalamic norepinephrine and serotonin levels were elevated in hyperinsulinemic and insulin-resistant animals. Treatment with insulin was associated with restoration of hypothalamic neurotransmitter abnormalities, indicating that ventromedial hypothalamus dysfunction can impair pancreatic beta cells resulting in metabolic abnormalities consistent with MS. Treatment with omega-3 fatty acids, beta blockers, ACE inhibitors, estrogen, and meditation may have a beneficial effect on insulin receptors and ventromedial hypothalamic dysfunction. However, no definite or precise insight into the pathophysiological link between MS, brain function and nutrition is available. Despite this, epidemiological studies and intervention trials indicate that treatment with n-3 fatty acids may be adopted in clinical practice and used to direct therapy for prevention of type 2 diabetes, hypertension, coronary artery disease (CAD), and atherosclerosis, thereby indicating that MS may also respond to this treatment.
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PMID:Can brain dysfunction be a predisposing factor for metabolic syndrome? 1575 41

The spiropiperidine, MK0677, has been exploited to characterize and expression clone the growth hormone secretagogue receptor (GHS-R). Cloning of this receptor led to identification of its natural ligands, ghrelin and adenosine. Targeted disruption of the Ghsr gene demonstrated unambiguously that the GH-releasing and orexigenic properties of ghrelin are dependent on Ghsr expression and that the orexigenic signal is mediated through neuropeptide Y and agouti-related peptide neurons. This review summarizes new developments in our understanding of the physiological roles of ghrelin and its receptor (GHS-R). Recent discoveries of the effects of ghrelin on the thymus and proinflammatory and chemotactic cytokine pathways stimulate renewed interest in potential clinical applications, which include age-associated disorders, such as metabolic disease, sarcopenia, congestive heart failure, atherosclerosis and anorexia.
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PMID:Developments in ghrelin biology and potential clinical relevance. 1621 42

Adipose tissue plays a critical role in energy homeostasis, not only in storing triglycerides, but also responding to nutrient, neural, and hormonal signals and secreting adipokines that control feeding, thermogenesis, immunity, and neuroendocrine function. A rise in leptin signals satiety to the brain through receptors in hypothalamic and brainstem neurons. Leptin activates tyrosine kinase, Janus kinase 2, and signal transducer and activator of transcription 3, leading to increased levels of anorexigenic peptides, e.g., alpha-melanocyte stimulating hormone and cocaine- and amphetamine-regulated transcript, and inhibition of orexigenic peptides, e.g., neuropeptide Y and agouti-related peptide. Obesity is characterized by hyperleptinemia and hypothalamic leptin resistance, partly caused by induction of suppressor of cytokine signaling-3. Leptin falls rapidly during fasting and potently stimulates appetite, reduces thermogenesis, and mediates the inhibition of thyroid and reproductive hormones and activation of the hypothalamic-pituitary-adrenal axis. These actions are integrated by the paraventicular hypothalamic nucleus. Leptin also decreases glucose and stimulates lipolysis through central and peripheral pathways involving AMP-activated protein kinase (AMPK). Adiponectin is secreted exclusively by adipocytes and has been linked to glucose, lipid, and cardiovascular regulation. Obesity, diabetes, and atherosclerosis have been associated with reduced adiponectin levels, whereas adiponectin treatment reverses these abnormalities partly through activation of AMPK in liver and muscle. Administration of adiponectin in the brain recapitulates the peripheral actions to increase fatty acid oxidation and insulin sensitivity and reduce glucose. Although putative adiponectin receptors are widespread in peripheral organs and brain, it is uncertain whether adiponectin acts exclusively through these targets. As with leptin, adiponectin requires the central melanocortin pathway. Furthermore, adiponectin stimulates fatty acid oxidation and reduces glucose and lipids, at least in part, by activating AMPK in muscle and liver.
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PMID:Adipose tissue as an endocrine organ. 1702 75

Sympathetic neurotransmitter neuropeptide Y (NPY) is associated with vascular remodelling, neointimal hyperplasia and atherosclerosis in experimental animal models and clinical studies. In order to study the role of sympathetic nerve-produced NPY in vascular diseases, transgenic mouse model overexpressing NPY in central and peripheral noradrenergic neurons under the dopamine-beta-hydroxylase (DBH) promoter was recently created (OE-NPY(DBH) mouse). This study aimed to examine the effect of NPY overexpression on arterial neointimal hyperplasia in an experimental model of vascular injury. Transgenic OE-NPY(DBH) mice and wildtype control mice of two different inbred strains (C57BL/6 and FVB/n) underwent a femoral artery surgery with a transluminar injury by a 0.38-mm guide wire insertion. Arteries were harvested 4 weeks from the surgery, and they were stained for basic morphology. Both strains of OE-NPY(DBH) mice, as compared with wildtype control mice, showed on average 50% greater formation of the neointima (P<0.01) and an increase in the medial area (P=0.05). The results suggest that moderately increased neuronal NPY causes the arteries to be more susceptible to femoral artery thickening after endothelial injury. The OE-NPY(DBH) mouse provides a novel tool to explore the role of NPY in the development of vascular disease related to metabolic disorders.
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PMID:Sympathetic nervous system-targeted neuropeptide Y overexpression in mice enhances neointimal formation in response to vascular injury. 1913 90


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