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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We analyzed the evolution with age of the frequencies of the I/D polymorphism of the angiotensin I-converting enzyme (ACE), a1166c of the angiotensin II AT1 receptor (AT1R), M235T of the angiotensinogen (AGT) and A225V of their methylenetetrahydrofolate reductase (MTHFR) gene in a healthy (H) population and the subsequent comparison to age- and sex-matched groups of myocardial infarction (MI) subjects. A total of 472 H subjects were divided into three groups < 30, 30-55 and > 55 years old and 277 individuals with MI into two groups 30-55 and > 55 years old. The evolution with age showed that the AGT M allele (P < 0.001) and the MTHFR V allele (P < 0.05) frequency decreased with age in H men. The comparison between healthy and MI groups showed that the MM genotype frequency increased in MI men > 55 years (OR =4.16; 95% CI; 1.72-10.1) The cc genotype showed a similar behaviour (OR = 3.96; 95% CI; 1.21-12.9). In men, all the combinations with MM genotype presented a high risk, with OR values between 1.10 and 7.22. In women, the cc genotype increased in the MI > 55 group (OR = 6.66; 95% CI; 2.02-21.9). All the combinations with the cc genotype showed OR values between 1.71 and 13.3. The MM genotype in men and cc genotype in men and women, are independent risk factors for MI. We propose that the study of the allele frequency evolution in an H population at different ages is essential to determine risk factors for MI in case-control studies, since data from isolated age-matched groups can be misinterpreted.
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PMID:The genotype interactions of methylenetetrahydrofolate reductase and renin-angiotensin system genes are associated with myocardial infarction. 1048 56

Recent developments in molecular biological techniques allowed us to examine the genetic risk factors responsible for essential hypertension. The candidate gene approach revealed that several gene polymorphisms increase the relative risk for hypertension. Most genetic studies, however, examined only young subjects but not elderly ones. To examine the importance of gene polymorphisms in elderly hypertension, we carried out a case-control study and compared the odds ratio for hypertension between young (< 60) and elderly (> or = 60) subjects. The participants of this study were recruited from the outpatients of Osaka University Medical School with informed consent. We examined the following polymorphisms as candidates: the angiotensinogen (AGT/M235T), angiotensin converting enzyme (ACE I/D), angiotensin II type 1 (AT1/A1166C) and type 2 (AT2/C3123A) receptors, alpha-adducin (adducin/Gly460Trp), methylenetetrahydrofolate reductase (MTHHR/C677T), and apolipoprotein (apoE/epsilon 4, apoE/T-491A). In young subjects, the AGT/T235 allele significantly increased the odds ratio for hypertension but not in elderly subjects. In young males, the AT2/A3123 allele was also associated with hypertension but not in females or in elderly subjects. Other associations between polymorphism and hypertension did not reach a significant level. To sum up, it was revealed that some polymorphisms increase the susceptibility for hypertension but others do not, which suggests that there is heterogeneity in the genetic involvement of polymorphism due to aging.
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PMID:[Genetic analysis of candidate gene polymorphisms in elderly hypertension]. 1055 62

It is most unlikely that there is a single 'pre-eclampsia (PE) gene'. We are probably looking for a cluster of polymorphisms which, possibly in conjunction with environmental factors, predispose to the development of the condition. Accurate phenotyping is vital for any genetic studies of PE, and since the disease is only clinically-detectable in the second half of pregnancy, is particularly difficult. It is increasingly likely that there is a fetal genetic contribution which can only be examined after birth. Candidate genes examined on the basis of displayed or hypothetical pathophysiological effects, but for which no evidence of association or linkage has been found have included HLA-DRbeta, HLA-G, and tumour necrosis factor alpha (chromosome 6), angiotensin-converting enzyme (chromosome 17) and CuZn superoxide dismutase (chromosome 21). Chromosomal exclusion mapping and a pedigree study suggest a role for genes on chromosomes 1, 3, 4, 9 or 18. Two genes concerned with clotting, those for factor 5 and methylenetetrahydrofolate reductase, lie on chromosome 1. Both have polymorphisms present in significantly higher frequency in women with PE, as well as showing functional abnormality. They probably predispose to the development of the condition, without being necessary for it. The angiotensinogen (Aogen) gene also lies on chromosome 1. The renin-angiotensin system may be activated during the early stages of PE and subsequently suppressed. In some populations, a relatively common polymorphism is present in raised frequency in women with PE, but it is also raised in non-pregnant hypertensive subjects. However, it is in partial linkage disequilibrium with another polymorphism which shows significantly distorted transmission from mother to fetus in PE pregnancies. Furthermore, its expression is significantly raised in the decidual spiral arteries; abnormal placentation is a feature of PE. We have also shown that a relatively common polymorphism in the angiotensin AT1 receptor gene (chromosome 3) is associated with raised density of the receptor. Thus far, studies of candidate genes have been on a small scale and have very much reflected the pathophysiological research interests of the investigators. The multifaceted nature of PE and the difficulties of accurate phenotyping require the accumulation of a large, very carefully phenotyped, database. It is hoped that funding will become available this year in the UK to allow the collection of such a database. The introduction of chip technology should allow genome scanning of the resource.
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PMID:What is the place of genetics in the pathogenesis of pre-eclampsia? 1056 60

Because of the importance of the renin-angiotensin system in the pathophysiology of hypertension and in mediating associated alterations in renal function, angiotensin II (Ang II) AT1 receptor blockers provide a direct means of protecting against influences of excessive Ang II levels. The kidney is an important site of action of Ang II AT1 receptor blockers because intrarenal Ang II not only vasoconstricts the renal vasculature but also reduces sodium excretion and suppresses the pressure natriuresis relationship. Even in normal conditions, intrarenal Ang II content is greater than can be explained on the basis of circulating Ang II and is compartmentalized with proximal tubule concentrations of Ang I and Ang II being several times higher than plasma concentrations. The localization of angiotensinogen in proximal tubule cells further supports the concept that the proximal tubule secretes Ang II or precursors of Ang II into the tubular fluid to activate luminal Ang II receptors. Recent immunohistochemical studies have demonstrated an abundance of AT1 receptors on the luminal surface of proximal and distal tubule cells as well as on vascular smooth muscle cells of afferent and efferent arterioles and on glomerular mesangial cells. Activation of luminal AT1 receptors stimulates the sodium hydrogen exchanger and increases reabsorption rate. The prominence of AT1 receptors in vascular and epithelial tissues in the kidney provides the basis for the powerful effects of AT1 receptor blockers on renal function especially in hypertensive conditions. In the two-kidney, one-clip (2K1C) Goldblatt hypertensive rat model, the nonclipped kidney is renin depleted but the intrarenal Ang II levels are not suppressed and Ang II concentrations in proximal tubular fluid remain high (10(-8) mol/L). AT1 receptor blockers such as candesartan have been shown to cause significant increases in glomerular filtration rate, renal blood flow and proportionately much greater increases in sodium excretion and fractional sodium excretion. Ang II blockade also markedly increases the slope of the pressure natriuresis relationship. The collective actions of Ang II blockers on tubular transport and renal hemodynamics provide long-term effects to regulate sodium balance, which contributes to the long-term control of hypertension.
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PMID:Renal responses to AT1 receptor blockade. 1067 88

Conditioned medium of cardiac fibroblasts was found to induce protein synthesis and signal transduction events rapidly, and to increase angiotensinogen messenger RNA (mRNA) levels in neonatal rat ventricular myocytes. Within 4 hours, fibroblast-conditioned medium (FCM) stimulated protein synthesis in cardiac myocytes, independent of the contractile state, and induced marked increases within 24 hours in total protein content. Endothelin- released by cardiac fibroblasts was not responsible for the stimulation of protein synthesis. FCM rapidly activated signal transduction events in cardiac myocytes associated with hypertrophic stimuli, including: (1) increased tyrosine phosphorylation of several prominent protein bands; (2) mitogen-activated protein kinases (ERK 1 and ERK 2); and (3) protein kinase C. Finally, FCM caused an increase at 8 hours in angiotensinogen mRNA levels of cardiac myocytes, whereas no effect was observed on mRNA levels for renin or the type 1 angiotensin II receptor (AT1). Our results suggest that cardiac fibroblasts produce a factor that rapidly activates cardiac myocyte growth through a membrane receptor that couples to conventional signal transduction pathways.
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PMID:Paracrine actions of cardiac fibroblasts on cardiomyocytes: implications for the cardiac renin-angiotensin system. 1075 May 86

Evidence for the existence of an intrinsic angiotensin system based on locally formed angiotensinogen as a precursor for angiotensin production has been demonstrated in the rat epididymis. The data strongly support the presence of an epididymal renin-angiotensin system (RAS) which may be important for epididymal and sperm functions. In the present study, the effects of castration and testicular hormonal replacement on the expression of RAS components from the rat epididymis are investigated at the gene and protein levels. Results from northern blot and western blot analyses consistently showed that the expression of angiotensinogen mRNA and protein was apparently abolished by castration whereas their expression was completely restored to control levels when the castrated rats were hormonally replaced with either testosterone alone or with combined testosterone and estradiol. Northern blot did not detect any signal for angiotensinogen mRNA while western blot could detect a weak signal for angiotensinogen protein when the castrated rats were replaced with estradiol alone. Renin could be detected neither in control, castrated nor hormonally replaced rats. Moreover, the expression of angiotensin II receptor, type I (AT1) was almost abolished by castration as demonstrated by northern blot and reverse transcription-polymerase chain reaction. These data indicate that the expression of RAS by the rat epididymis at the levels of its precursor angiotensinogen and its receptor AT1, is subject to the regulation of testicular hormones and its expression appears to be predominantly testosterone-dependent.
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PMID:Testicular hormonal regulation of the renin-angiotensin system in the rat epididymis. 1075 67

To determine whether myocyte death and angiotensin II (AT II) formation are implicated in the development of diabetic cardiomyopathy, rats were injected with streptozotocin, and apoptosis and necrosis were measured at 3, 10, and 28 days. Expression of the components of the renin-angiotensin system (RAS) and AT II levels were assessed at 3 days. The percentage of AT II-labeled myocytes and the number and distribution of AT II sites in myocytes were measured at 3 and 10 days. The effects of AT1 blockade on local RAS and cell death were examined at 3 days. Diabetes was characterized by myocyte apoptosis that peaked at 3 days and decreased at 10 and 28 days, in spite of high concentrations of blood glucose. Cell necrosis was absent throughout. Angiotensinogen, renin, and AT1 receptor increased in myocytes from diabetic rat hearts, while angiotensin-converting enzyme and AT2 remained constant. AT II quantity increased severalfold, as did the fraction of AT II positive cells and the number of AT II sites per myocyte. However, AT II labeling decreased at 10 days, which paralleled the reduction in myocyte death. AT1 antagonist inhibited upregulation of this receptor and angiotensinogen, which prevented AT II synthesis and myocyte death at their peaks with diabetes. An aggregate 30% myocyte loss and a 14% increase in the volume of viable cells were found in diabetic rats at 28 days. Thus diabetic cardiomyopathy may be viewed as an AT II-dependent process in which that peptide plays a critical role in myocyte death and hypertrophy.
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PMID:Myocyte death in streptozotocin-induced diabetes in rats in angiotensin II- dependent. 1078 Jun 68

A number of kidney diseases, and their progression to end-stage renal disease, are driven, in part, by the effects of angiotensin II. Increasing levels of angiotensin II may in turn up-regulate the expression of growth factors and cytokines, such as transforming growth factor-beta1 (TGF-beta1), tumor necrosis factor-alpha (TNF-alpha), osteopontin, vascular cell adhesion molecule-1 (VCAM-1), nuclear factor-kappaB (NF-kappaB), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and insulin-like growth factor. Most of these compounds promote cell growth and fibrosis. Angiotensin II also stimulates oxidative stress. This stress in turn may potentiate the vasoconstrictor effect of the peptide due, in part, to increased catabolism of nitric oxide (NO). Oxidative stress, fueled in part by angiotensin II, up-regulates the expression of adhesion molecules, chemoattractant compounds and cytokines. The angiotensinogen gene, which provides the precursor for angiotensin production, is stimulated by NF-kappaB activation. NF-kappaB is activated by angiotensin in the liver and in the kidney. This provides an autocrine reinforcing loop that up-regulates angiotensin production. Angiotensin II activates NF-kappaB through both AT1 and AT2 receptors. In addition, angiotensin-converting enzyme (ACE) inhibition markedly decreases NF-kappaB activation in the setting of renal disease.
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PMID:The role of vasoactive compounds, growth factors and cytokines in the progression of renal disease. 1082 55

Essential Hypertension (EH) is a multifactorial and polygenic syndrome with a high impact in public health. Recently, rare mendelian forms of hypertension such as glucocorticoid-remediable aldosteronism (GRA), apparent mineralocorticoid excess (AME) and Liddle Syndrome caused by single gene mutations have been identified in which the mechanism is an increased sodium retention. Therefore, it is tempting to speculate that the most common forms of EH may be due to diverse highly prevalent molecular variants of susceptibility genes with low penetrance that are involved in arterial blood pressure (ABP) and electrolytic balance. Although a number of candidate genes such as NO synthases, ANP, ion transporters, adducins, LDL receptor, etc. can participate, renin-angiotensin system components are the most extensively studied. Although not associated with EH, the ACE D allele seems to confer a high risk of CHD or LVH. Angiotensinogen 235T and 174M variants are more likely associated with EH and positively correlate with clinical or ambulatory ABP in adolescents or adults. Individuals who carry these angiotensinogen alleles would be at 1.4 higher risk of suffering EH than homozygotes for M235 or T174 alleles. Associations of AT1 receptor variants with EH remain to be definitively defined. In conclusion, the characterization of the genetic background, although difficult at the present time, may have clear benefits in terms of defining a more rational therapy and prevention in individuals at risk. Even though this aim seems difficult to achieve since more than 150 candidate genes have been postulated as the cause of EH, with 6 to 10 SNPs in each of them, new technologies such as DNA micro-arrays will provide us with the opportunity to analyse the total genetic risk in each subject.
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PMID:[Molecular genetics of essential hypertension. Susceptibility and resistance genes]. 1083 1

Transgenic mice are useful tools to investigate the mechanisms of the renal profibrotic actions of endothelin and angiotensin II. The overexpression of angiotensinogen and renin genes induces renal sclerosis independently of changes in systemic hemodynamics. The same results are observed when the endothelin-1 gene is overexpressed. Transgenic mice harboring the luciferase gene, under the control of the collagen I alpha2 chain promoter, and made hypertensive by induction of a nitric oxide (NO) deficiency have been studied. In this strain of mice, luciferase activity is an early index of renal and vascular fibrosis. Luciferase activity was increased in preglomerular arterioles and glomeruli when mice were treated with N:(omega)-nitro-L-arginine methyl ester, an inhibitor of NO synthases. Bosentan (an endothelin receptor antagonist) was as efficient as losartan (an AT1 receptor antagonist) in preventing renal fibrosis, although it did not decrease BP. In short-term experiments, angiotensin II produced an increase in luciferase activity that was entirely prevented by losartan but also by bosentan. It can be concluded that, during chronic inhibition of NO, the collagen I gene is activated, which contributes to the development of nephroangiosclerosis and glomerulosclerosis. Angiotensin II plays a major role in this fibrogenic process, and its effect is at least partly independent of systemic hemodynamics and mediated by the profibrotic action of endothelin-1.
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PMID:Mechanisms mediating the renal profibrotic actions of vasoactive peptides in transgenic mice. 1106 43


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