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)

1. Ghrelin is the recently identified endogenous ligand for the cloned growth hormone secretagogue receptor (GHS-R). We have characterized for the first time the binding of human [125I-His(9)]-ghrelin to normal human and rat tissue and demonstrated expression of this 'orphan' receptor that has previously been predicted to exist from mRNA. Furthermore, we have discovered that [125I-His(9)]-ghrelin density is significantly increased in atherosclerosis. 2. [125I-His(9)]-Ghrelin bound to non-diseased human heart (left ventricle) with an association rate constant (k(obs)) of 0.16+/-0.004 min(-1), a dissociation rate constant of 0.068+/-0.0005 min(-1) (kinetically derived K(D) of 0.1 nM; n=5 individuals+/-s.e.mean), a K(D) of 0.43+/-0.08 nM and B(max) of 7.8+/-0.9 fmol mg(-1) protein (n=6 individual+/-s.e.mean). 3. Specific [125I-His(9)]-ghrelin binding was to the human vasculature including aorta, coronary, pulmonary, arcuate arteries in the kidney and saphenous veins. In rat tissues, binding sites were also localized to the vasculature in peripheral tissues as well as the granular layer of the cerebellum in the CNS. 4. [125I-His(9)]-Ghrelin binding was significantly up-regulated (3 - 4 fold) in both atherosclerotic coronary arteries and saphenous vein grafts with advanced intimal thickening, compared with normal vessels (P<0.05). 5. Our results suggest that the native receptor for [125I-His(9)]-ghrelin may be widely distributed in the human cardiovascular system. Furthermore, changes in the density of this proposed ghrelin receptor implicates this new transmitter system in the development of atherosclerosis and may therefore represent a novel therapeutic target in the treatment of cardiovascular disease.
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PMID:[125I-His(9)]-ghrelin, a novel radioligand for localizing GHS orphan receptors in human and rat tissue: up-regulation of receptors with athersclerosis. 1152 6

The leucine 7 to proline 7 (Leu7Pro) polymorphism in the signal peptide of NPY is associated with high blood lipid concentrations and accelerated rate of atherosclerosis as well as diabetic retinopathy. Also, healthy subjects with this polymorphism have increased NPY secretion during sympathetic stimulation. Because NPY may regulate GH release and ghrelin may regulate NPY formation, we studied the effects of the Leu7/Pro7 genotype on GH, ghrelin, and IGF-I secretion during standardized cycle-ergometer exercise. Furthermore, we studied the effect of the Leu7/Pro7 genotype on diurnal GH secretion in rest in a separate study. The subjects with Leu7/Pro7 genotype had 54% higher maximal increases in the plasma GH concentrations than the controls during exercise. There were no significant differences in the ghrelin or IGF-I concentrations during exercise among the groups. Furthermore, there were no differences in diurnal GH secretion between the genotypes. The results indicate that the prepro-NPY genotype has an influence on GH response during exercise in humans. The clinical significance of this finding is not known, and further studies are needed to evaluate whether the observed change in GH secretion during exercise could play a role in promoting diseases.
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PMID:Enhanced exercise-induced GH secretion in subjects with Pro7 substitution in the prepro-NPY. 1170 4

Using novel synthetic radioligands, we have discovered receptors for the recently paired apelin (APJ orphan receptor), ghrelin (GHS orphan receptor), and urotensin II (orphan GPR14) in the human cardiovascular system and determined their anatomical localisation. In addition, we have established functional vasoactive properties for these three peptides as potential vasoconstrictor/vasodilator mediators and provided evidence for alteration of receptor density in cardiovascular disease. We find that receptors for apelin, ghrelin, and urotensin II are widely distributed in human cardiovascular tissue, suggesting perhaps vasoactive roles for these peptides in human vascular physiology and a potential role in pathophysiology. Apelin and urotensin II are potent vasoconstrictors with low efficacy, consistent with their low receptor density. Ghrelin receptor density was increased (approximately three- to fourfold) with atherosclerosis of coronary artery disease and accelerated atherosclerosis of saphenous vein grafts, compared with normal vessels, highlighting a potentially beneficial role for this novel vasodilator peptide in human vascular disease. Our approach has demonstrated one successful strategy for translating genetic information encoding recently paired orphan receptor ligands into discovery of function. This study has the advantage of focussing on the actual disease processes, which allow the more precise identification of novel therapeutic targets.
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PMID:Discovery of recently adopted orphan receptors for apelin, urotensin II, and ghrelin identified using novel radioligands and functional role in the human cardiovascular system. 1205 41

Endothelin (ET)-1 and thromboxane (Tx) levels are increased in human atherosclerosis. One of the aims of this study was to understand how receptors for a peptide mediator (ET-1) with a long physiological half life, would differ from a lipid mediator (TxA(2)), with a short physiological half life, in human coronary artery disease (CAD). Secondly, to determine if receptor protein is present in human coronary artery vascular smooth muscle for the recently adopted peptide orphan receptors for urotensin-II, apelin and ghrelin. The ET(A) receptor subtype predominated in the medial smooth muscle layer of both non-diseased coronary artery (NCA) and CAD. However, this subtype was present at relatively low density in the proliferated intimal layer of CAD. The ET(B) receptor protein was not altered with CAD, compared with NCA. Tx receptor density was significantly (P<0.05) increased in both the media and intima of CAD, compared with NCA. There was no alteration in receptor density, on the medial smooth muscle for urotensin-II and apelin with CAD. Interestingly, receptor density for the novel vasodilator peptide ghrelin was significantly (P<0.05) increased (approx. 4 fold) with CAD, compared with NCA. The alteration of receptor density with disease for Tx and ghrelin provides novel therapeutic targets for the treatment of atherosclerosis. In conclusion, while some GPCR are altered, others remain unchanged with human atherosclerosis. The increase in vasoconstrictor Tx receptor density with disease suggests the importance of Tx receptor antagonism. Intriguingly, the increase in receptor density for the novel vasodilator ghrelin, identified from post-genomic research, may potentially be beneficial with human atherosclerosis.
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PMID:G-protein-coupled receptors in human atherosclerosis: comparison of vasoconstrictors (endothelin and thromboxane) with recently de-orphanized (urotensin-II, apelin and ghrelin) receptors. 1219 79

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

Experimental studies have suggested that ghrelin plays a role in glucose homeostasis and in the regulation of blood pressure (BP). We therefore assessed the hypothesis that a low ghrelin concentration may be a risk factor for type 2 diabetes and hypertension. We also characterized the effect of the ghrelin Arg51Gln and Leu72Met mutations on ghrelin concentrations in the population-based hypertensive (n = 519) and control (n = 526) cohorts of our OPERA (Oulu Project Elucidating Risk of Atherosclerosis) study. The fasting plasma ghrelin concentrations of 1,040 subjects were analyzed using the radioimmunoassay method. Insulin sensitivity was assessed using the quantitative insulin sensitivity check index (QUICKI). Ghrelin concentrations were negatively associated with fasting insulin (P < 0.001), systolic (P = 0.026) and diastolic BP (P = 0.018), and the prevalence of type 2 diabetes (P = 0.015) and insulin resistance (P < 0.001) in the multivariate models. In the control cohort, low ghrelin was associated with hypertension (BP >140/90 mmHg) (P = 0.031). The subjects with the ghrelin 51Gln allele had lower ghrelin concentrations than the Arg51Arg homozygotes (P = 0.001). We conclude that low ghrelin is independently associated with type 2 diabetes, insulin concentration, insulin resistance, and elevated BP. Therefore, it might have some role in the etiology of type 2 diabetes and the regulation of BP. The ghrelin Arg51Gln mutation is associated with low plasma ghrelin concentrations.
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PMID:Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes. 1451 39

Systemic thermal therapy, such as taking a warm-water bath and sauna, induces systemic vasodilation. It was found that repeated sauna therapy (60 degrees C for 15 min) improved hemodynamic parameters, clinical symptoms, cardiac function, and vascular endothelial function in patients with congestive heart failure. Vascular endothelial function is impaired in subjects with lifestyle-related diseases, such as hypertension, hyperlipidemia, diabetes mellitus, obesity, and smoking. Sauna therapy also improved endothelial dysfunction in these subjects, suggesting a preventive role for atherosclerosis. In animal experiments, sauna therapy increases mRNA and protein levels of endothelial nitric oxide synthase (eNOS) in aortas. In normal-weight patients with appetite loss, repeated sauna therapy increased plasma ghrelin concentrations and daily caloric intake and improved feeding behavior. In obese patients, the body weight and body fat significantly decreased after 2 weeks of sauna therapy without increase of plasma ghrelin concentrations. On the basis of these data, sauna therapy may be a promising therapy for patients with lifestyle-related diseases.
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PMID:Clinical implications of thermal therapy in lifestyle-related diseases. 1461 Feb 68

Leptin and ghrelin are novel peptide hormones which are counter-regulatory in the central control of appetite. More recently, it has become clear that these hormones have a range of effects on the cardiovascular system. Leptin increases sympathetic activity, producing a pressor effect when acting on the central nervous system. However, leptin produces vasodilation by an endothelium-dependent mechanism peripherally. Ghrelin decreases sympathetic activity and has a depressor effect when acting on the central nervous system. Peripherally, ghrelin produces vasodilation by an endothelium-independent mechanism. Ghrelin improves left ventricular function and cardiac cachexia in heart failure. Leptin may contribute to cardiac cachexia, and to obesity-related cardiomyopathy by a variety of mechanisms. Leptin has pro-inflammatory, proliferative and calcification promoting effects in the vasculature. Ghrelin has recently been shown to be anti-inflammatory in the vasculature. Leptin may also produce a pro-thrombotic state through stimulation of platelet aggregation and inhibition of coagulation and fibrinolysis. The evidence for and against these effects as well as their pathophysiological significance in obesity hypertension, heart failure, atherosclerosis and thrombosis are discussed.
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PMID:The emerging roles of leptin and ghrelin in cardiovascular physiology and pathophysiology. 1585 36

1. In the present study, we sought to determine whether physiological or pathophysiological concentrations of obesity related peptides influence the key early atherogenic events of monocyte adhesion to endothelial cells and adhesion molecule expression using primary human cells. 2. Human umbilical vein endothelial cells were grown to confluence and human monocytes were obtained by elutriation. Adhesion was assessed by automated cell counting and cell adhesion molecule expression (E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)) was assayed by ELISA. 3. Experimental conditions included untreated control, ghrelin (100, 150, 450 and 1350 pmol/L), resistin (15, 40 and 100 ng/mL) and combined leptin and insulin (combinations of 30 and 120 pmol/L insulin and 5, 50 and 500 ng/mL leptin). 4. Both resistin and ghrelin produced modest but significant increases in VCAM-1 expression (110 +/- 4 and 117 +/- 13% compared with controls, respectively; both P <or= 0.01). Ghrelin also increased ICAM-1 expression (119 +/- 17% of control; P <or= 0.01). 5. However, despite these increases in adhesion molecule expression, neither ghrelin nor resistin altered monocyte adhesion values. 6. Neither leptin nor insulin altered monocyte adhesion to endothelial cells or cell adhesion molecule expression. 7. Pathophysiologically relevant concentrations of ghrelin and resistin, within the range of concentrations exhibited by patients with anorexia nervosa or the Prader-Willi syndrome and type 2 diabetes, respectively, increase endothelial cell adhesion molecule expression, possibly contributing to increased atherosclerosis risk in such subjects.
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PMID:Pathophysiological levels of the obesity related peptides resistin and ghrelin increase adhesion molecule expression on human vascular endothelial cells. 1617 45

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


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