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)

The second messenger cyclic guanosine 5'-monophosphate (cGMP) plays a key role in the control and regulation of a steadily increasing number of diverse physiological processes. As the appreciation of the importance of understanding the cGMP signaling pathway has grown, so has the awareness of the limited techniques with which to study the rapid intracellular cGMP kinetics. We have previously demonstrated the construction of cygnets, cGMP indicators using energy transfer comprised of cyan and yellow variants of green fluorescent protein flanked by conformationally sensitive cGMP receptor portion taken from the cGMP-dependent protein kinase. Here, we report that cGMP binds to Cygnet-2.1, utilizing ECFP and Citrine, with an apparent equilibrium-binding constant of 600 nM causing a total fluorescence intensity ratio change of 45%. In contrast, cAMP could elicit a maximal 10% change in fluorescence resonance energy transfer (FRET) ratio, demonstrating an approx 500-fold selectivity for cGMP. When expressed in vascular smooth muscle cells, cygnets demonstrated even cytosolic distribution and nuclear exclusion. Cultured rat aortic smooth muscle cells, which exhibit a noncontractile, synthetic phenotype typically seen in response to atherosclerosis or vascular injury, responded to natriuretic peptide (BNP)-mediated activation of the particulate guanylyl cyclase. In conclusion, cygnets have facilitated the temporal resolution and evaluation of the contributions of cyclases and phosphodiesterases in determining overall cGMP accumulation, and the visualization of novel spatial dynamics that will contribute to more fully understanding the role of cGMP in the mediation of smooth muscle relaxation.
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PMID:Cygnets: in vivo characterization of novel cGMP indicators and in vivo imaging of intracellular cGMP. 1598 53

Understanding restenosis after percutaneous coronary intervention (PCI) remains a challenge. Neointimal proliferation is the main cause of restenosis. C-Type natriuretic peptide (CNP) plays a role in relaxation and growth inhibition of vascular smooth muscle cells (SMCs); the effects depend on the presence of specific natriuretic peptide receptors (NPRs) consisting of NPR-A, NPR-B, and NPR-C. To test the hypothesis that CNP and NPRs may be involved in restenosis, we immunohistochemically studied the expression of CNP and NPRs during the post-PCI healing process; 10 sites after PCI obtained at autopsy and 14 atherectomy specimens obtained from restenotic sites were investigated. Frozen sections were stained with antibodies against CNP, NPRs, SMCs, macrophages, and endothelial cells. Within 2 months after PCI, most neointimal SMCs expressed CNP and NPR-A. The expression of CNP and NPR-A in these neointimal SMCs decreased from 6 months onward. In contrast, NPR-C was strongly expressed in neointimal SMCs from 1 to 9 months after PCI. In atherectomy specimens, most neointimal SMCs showed weak positivity for CNP and NPR-A, but NPR-C was strongly expressed in the neointimal SMCs. These findings strongly suggest that a paracrine and autocrine system of CNP and NPRs may be important in controlling neointimal growth after PCI in humans.
Atherosclerosis 2005 Aug
PMID:C-Type natriuretic peptide and natriuretic peptide receptors are expressed by smooth muscle cells in the neointima after percutaneous coronary intervention. 1603 77

Elevated plasma levels of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP) are seen in the setting of cardiac ischemia and are associated with adverse outcomes in patients with coronary artery disease. The mechanisms leading to natriuretic peptide elevation in patients with coronary artery disease, including the contribution of coronary atherosclerosis itself, have not been fully elucidated. Measurement of NT-pro-BNP, electron beam computed tomography, and cardiac magnetic resonance imaging were performed in 2,445 subjects from the Dallas Heart Study who were free of heart failure and renal insufficiency. Electron beam computed tomography-determined coronary artery calcium scores were categorized as none (<10), mild (> or =10 to <100), moderate (> or =100 to <400), and severe (> or =400). NT-pro-BNP levels increased significantly across increasing coronary artery calcium score categories (p <0.0001 for trend). In multivariate models adjusted for age, gender, race, body mass index, hypertension, history of myocardial infarction, angina, angiotensin-converting enzyme inhibitor use, beta-blocker use, left ventricular (LV) ejection fraction, and LV mass, higher coronary artery calcium scores remained independently associated with higher log NT-pro-BNP levels (p = 0.03). This association persisted in similar models excluding patients with low LV ejection fractions, LV hypertrophy, angina pectoris, and a history of myocardial infarction. In conclusion, these findings support the hypothesis that coronary atherosclerosis may directly influence the activation of the cardiac neurohormonal system.
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PMID:Relation of coronary atherosclerosis determined by electron beam computed tomography and plasma levels of n-terminal pro-brain natriuretic peptide in a multiethnic population-based sample (the Dallas Heart Study). 1625 99

Corin activates pro-A-type naturetic peptide and pro-B-type naturetic peptide into biologically active molecules. We recently identified a minor allele in the corin gene defined by 2 highly linked single nucleotide polymorphisms (T555I and Q568P), which was associated with hypertension in blacks. Because of the direct antihypertrophic effects of the natriuretic peptide system, we hypothesized that the minor corin I555(P568) allele would be associated with an enhanced hypertrophic response to pressure overload. The relationship between systolic blood pressure and indexed left ventricular mass, derived from cardiac MRI, was analyzed in the Dallas Heart Study as a function of corin allele status. The Multi-Ethnic Study of Atherosclerosis was used as a validation cohort. All of the analyses were limited to self-identified blacks without treatment for hypertension. In addition, we genotyped 2114 markers highly informative for African ancestry in the Dallas Heart Study and derived a covariate representing African ancestry for multivariate models. In adjusted analysis, the corin I555(P568) allele was an independent predictor of left-ventricular mass in subjects with elevated systolic blood pressure. Linear spline regression analysis confirmed a significant interaction (P=0.002) between the corin I555(P568) allele and systolic blood pressure as a predictor of left ventricular mass in subjects with systolic blood pressure >120 mm Hg, and this nonlinear interaction was replicated in the Multi-Ethnic Study of Atherosclerosis. In the Dallas Heart Study, the corin I555(P568) allele was also associated with an increased odds for prevalent left ventricular hypertrophy in the presence of untreated hypertension. These data suggest that the corin I555(P568) allele represents a cardiac hypertrophy-sensitizing genetic locus in systemic hypertension.
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PMID:Corin I555(P568) allele is associated with enhanced cardiac hypertrophic response to increased systemic afterload. 1730 58

Despite good outcomes in pediatric renal transplantation, life expectancy is reduced, mostly as a result of accelerated atherosclerosis. A comprehensive evaluation of cardiac status and risk factors for cardiovascular disease was performed in 60 patients after renal transplantation (age 3 to 29 yr; mean 15.8). Posttransplantation diabetes was diagnosed in 7%. Half of the patients did not engage in any physical activity, and this was associated with increased body mass index. Uncontrolled hypertension was found in 13% of patient, and 53% were on antihypertensive medications. BP index was associated with left ventricular mass index (LVMI). Dyslipidemia was relatively uncommon, with hypercholesterolemia found in 15% and elevated LDL cholesterol found in 10% of patients. Hyperhomocysteinemia was frequent (58%); in most patients, it was not due to folate or B(12) deficiency. Lipid and homocysteine abnormalities were associated with cyclosporine therapy. Echocardiography demonstrated normal LVMI in 93% of patients, although LVMI was higher than in healthy control subjects. Cardiac troponin I was normal in all patients, but N-terminal pro-brain natriuretic peptide was elevated in 35% and was associated with LVMI and renal function. Although present cardiac status is relatively normal in pediatric renal transplantation patients, cardiac risk factors are common, and strategies to prevent cardiovascular disease need to be developed.
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PMID:Risk factors for cardiovascular disease in children and young adults after renal transplantation. 1769 60

Pro-inflammatory cytokine over-expression may be implicated to the pathogenesis of anemia in chronic heart failure (CHF) through the suppression of bone marrow erythropoiesis. Erythropoietin administration has anti-inflammatory and anti-apoptotic properties in experimental CHF models and improves exercise capacity in anemic CHF patients. The present study investigates the effects of recombinant human erythropoietin analogue darbepoetin-alpha on circulating pro-inflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with CHF and anemia. Forty-one CHF patients (NYHA class: II-III; left ventricular (LV) ejection fraction (EF) <40%; hemoglobin <12.5g/dl; serum creatinine <2.5mg/dl) were randomized to receive either 3-month darbepoietin-* at 1.5 microg/kg every 20 days plus iron orally (n=21) or placebo plus iron orally (n=20). LV systolic function, plasma B-type natriuretic peptide (BNP), inflammatory markers (TNF-*, IL-6, CRP), anti-inflammatory cytokine IL-10, endothelial adhesion molecules (soluble ICAM-1 and VCAM-1) and soluble apoptosis mediators (soluble Fas, soluble Fas ligand), and 6-min walking distance were assessed at baseline and 3 months post-treatment. In darbepoetin-* treated patients, plasma BNP (451 (62-2770) from 802 (476-4440) pg/ml, p=0.002), IL-6 (6.5+/-4.7 from 10.5+/-7.8 pg/ml, p=0.013) and soluble Fas ligand (53.2+/-16.6 from 59.2+/-17.9 pg/ml, p=0.023) decreased significantly, while LVEF (32+/-6 from 26+/-6%, p<0.001), hemoglobin (12.8+/-1.4 from 10.9+/-1.0 g/dl, p<0.001) and 6-min walked distance (274+/-97 from 201+/-113m, p<0.01) increased significantly. No significant changes were observed in the placebo arm, except for a worsening in 6-min walked distance (p=0.044). In conclusion, darbepoetin-alpha reduces circulating pro-inflammatory cytokine IL-6 and apoptotic mediator soluble Fas ligand in CHF patients with anemia, with a parallel improvement of cardiac performance and exercise capacity.
Atherosclerosis 2008 Jul
PMID:Effects of darbepoetin-alpha on plasma pro-inflammatory cytokines, anti-inflammatory cytokine interleukin-10 and soluble Fas/Fas ligand system in anemic patients with chronic heart failure. 1799 71

Brain natriuretic peptide (BNP) level has been used as a marker of left ventricular (LV) systolic dysfunction (LVSD), even though some patients with atherosclerosis have a high BNP level irrespective of LV function. In this study, we investigate whether augmentation index (AI), which is an index of wave reflection, is involved in increasing BNP level in hypertensive patients without LVSD. Sixty treated hypertensive patients were enrolled in this study. Radial AI (r-AI) was measured in all patients. The patients were classified into tertiles on the basis of r-AI to identify the characteristics of the patients with a high r-AI. BNP level was significantly higher in the patients classified into the highest tertile of r-AI. In echocardiography, e', which is index of left ventricular (LV) diastolic function, decreased and LV mass index (LVMI) increased gradually with r-AI, whereas there was no difference in LV ejection fraction (LVEF). r-AI significantly correlated with LVMI (r=0.35, p<0.01) and e' (r=-0.30, p<0.05). In univariate analysis, age, heart rate, r-AI, LVEF, e' and LVMI were significantly correlated with BNP level, whereas multivariate analysis demonstrated that only r-AI and LVEF correlated with BNP level. In conclusion, an increase in r-AI was significantly associated with an increase in BNP level in hypertensive patients without LVSD. LV hypertrophy and diastolic dysfunction associated with increase in r-AI may be involved in increase in BNP level.
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PMID:Radial augmentation index associated with increase in B-type natriuretic peptide in patients with hypertension. 1817 56

Endothelial barrier dysfunction is a hallmark of many severe pathologies, including sepsis or atherosclerosis. The cardiovascular hormone atrial natriuretic peptide (ANP) has increasingly been suggested to counteract endothelial leakage. Surprisingly, the precise in vivo relevance of these observations has never been evaluated. Thus, we aimed to clarify this issue and, moreover, to identify the permeability-controlling subcellular systems that are targeted by ANP. Histamine was used as important pro-inflammatory, permeability-increasing stimulus. Measurements of fluorescein isothiocyanate (FITC)-dextran extravasation from venules of the mouse cremaster muscle and rat hematocrit values were performed to judge changes of endothelial permeability in vivo. It is noteworthy that ANP strongly reduced the histamine-evoked endothelial barrier dysfunction in vivo. In vitro, ANP blocked the breakdown of transendothelial electrical resistance (TEER) induced by histamine. Moreover, as judged by immunocytochemistry and Western blot analysis, ANP inhibited changes of vascular endothelial (VE)-cadherin, beta-catenin, and p120(ctn) morphology; VE-cadherin and myosin light chain 2 (MLC2) phosphorylation; and F-actin stress fiber formation. These changes seem to be predominantly mediated by the natriuretic peptide receptor (NPR)-A, but not by NPR-C. In summary, we revealed ANP as a potent endothelial barrier protecting agent in vivo and identified adherens junctions and the contractile apparatus as subcellular systems targeted by ANP. Thus, our study highlights ANP as an interesting pharmacological compound opening new therapeutic options for preventing endothelial leakage.
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PMID:Atrial natriuretic peptide protects against histamine-induced endothelial barrier dysfunction in vivo. 1841 63

Aortic valve sclerosis (AVS) may predispose to a prothrombotic state, as AVS is predictor of cardiovascular events in hypertensive populations. Thrombin exerts non-thrombotic effects such as vessel tone regulation, progression of atherosclerosis and stimulation of atrial natriuretic peptide (ANP) secretion. We hypothesized that hypertensive patients with AVS may have a persistently activated thrombin generation. We studied 234 asymptomatic never-treated hypertensive patients (73 of them with AVS). Prothrombin F1+2 (F1+2), as a marker of thrombin generation and fibrin D-dimer, as a marker of thrombus formation, ANP and brain natriuretic peptide (BNP) were measured. Presence of AVS, aortic jet velocity and left ventricular diameter at diastole were determined by echocardiography. Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease formula. F1+2 (median and interquartile range (IQR) = 1.05, 0.87-1.38 nM vs. 0.93, 0.72-1.16) and ANP (22, 14-37 pg ml(-1) vs. 17, 11-25) levels were greater, and glomerular filtration rate values (65+/-9 ml min(-1)/1.73 m2 vs. 68+/-11) were lower in hypertensive patients with AVS than in those without AVS. F1+2 (odds ratio, 95% CI = 2.94, 1.07-8.6) was independently associated with AVS after being adjusted for age, gender and the variables of cardiorenal functions measured. After 6 months of treatment using valsartan, F1+2 levels remained elevated in hypertensive patients with AVS (1.14, 0.83-1.42 nM vs. 1.07, 0.84-1.5, n=19), but decreased in those without AVS (1.01, 0.85-1.31 vs. 0.8, 0.84-1.78, n=27). Thrombin generation was associated with AVS in untreated hypertensive patients, and this association was persistent after blood-pressure-lowering treatment using valsartan.
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PMID:Association of aortic valve sclerosis with thrombin generation in hypertensive patients. 1870 26

C-type natriuretic peptide (CNP) is a member of Natriuretic peptides family which is synthesized and secreted by vascular endothelial cells. CNP can bind with specific G-protein coupling receptor -natriuretic peptide receptor-B (NPR-B) and elevate cellular cGMP level by activating guanylate cyclase. CNP regulates homeostasis of circulating system in an autocrine/paracrine manner. Vascular system, especially endothelium, is rich in CNP and its receptor. CNP exerts natriuretic and natriuretic effect and regulates vessel tone, inhibits migration and proliferation of vascular smooth muscle cell. CNP is tightly correlated with injured vascular diseases such as hypertension, atherosclerosis, thrombogenesis, restenosis and vascular calcification.
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PMID:[C-type natriuretic peptide and injured vascular diseases]. 1866 74


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