Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Hypertension is a serious risk factor for myocardial infarction, heart failure, vascular disease, stroke and renal failure. The incidence of hypertension is 25-30% in the adult Caucasian population and complications due to hypertension are even greater in African Americans. 2. The renin-angiotensin system plays an important role in the regulation of blood pressure and previous studies have suggested that angiotensinogen (AGT) gene locus is linked with human essential hypertension. Earlier studies suggested that a single nucleotide polymorphism (SNP) that converts methionine to threonine at amino acid 235 is associated with hypertension in the Caucasian population. However, this SNP is not associated with hypertension in African American and Chinese populations. 3. We have found an A/G polymorphism at -217 of the human AGT gene promoter and have shown that the frequency of allele A at -217 is significantly increased in the genomic DNA of African American hypertensive patients. 4. We have also shown that: (i) reporter constructs containing the AGT gene promoter with nucleoside A at -217 have increased promoter activity on transient transfection; and (ii) the CCAAT box enhancer binding protein (C/EBP) family of transcription factors and glucocorticoid receptor (GR) bind preferentially to this region of the promoter when nucleoside A is present at -217. In addition, variant -217A is always present with variants -532T, -793A and -1074T in the human AGT gene promoter. 5. These data suggest that the AGT haplotype containing -217A, -532T, -793A and -1074T may be involved in increased transcription of this gene and may play a role in human hypertension.
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PMID:A haplotype of the angiotensinogen gene is associated with hypertension in african americans. 1585 65

The renin-angiotensin-aldosterone system has functions that may contribute to brain infarction (BI). In 459 matched pairs of white patients and control subjects, we measured plasma angiotensin-converting enzyme (ACE) levels, seven polymorphisms (angiotensinogen T174M and M235T, ACE I/D and 4656 2/3CT repeat [rpt], angiotensin II type 1 receptor A1166C and A153G, and aldosterone synthase CYP11B2), and evaluated 5-year poststroke mortality. Mean plasma ACE levels (+/-standard error) were significantly greater in patients than control subjects (37.5 +/- 0.9 vs 33.9 +/- 0.9), in patients with lacunar stroke, and in patients with no previous vascular (cerebrovascular or cardiovascular) history. The risk for BI increased with tertiles of plasma ACE, without an interaction with hypertension. After adjustments, the association disappeared except among patients with cardioembolic BI and those without previous vascular events. Among the polymorphisms, there was a weak association of BI with angiotensin II type 1 receptor 1166C, a weak protective effect with angiotensinogen 174M, and a strong association of angiotensinogen 235T with 5-year vascular mortality. These results suggest that renin-angiotensin-aldosterone system activity and genes contribute to cerebrovascular disease and poststroke vascular death in white patients.
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PMID:Renin-angiotensin-aldosterone system in brain infarction and vascular death. 1598 9

Angiotensinogen is an essential component of the renin-angiotensin system. ACE-inhibitors and beta-blockers both have a direct influence on this system. To investigate whether the association between use of ACE-inhibitors or beta-blockers and the risk of myocardial infarction (MI) or stroke is modified by the T-allele of the angiotensinogen M235T polymorphism. In this study, 4097 subjects with hypertension , aged 55 years and older, were included from the Rotterdam Study, a population-based prospective cohort study in The Netherlands, from July 1, 1991 onwards. Follow-up ended at the diagnosis date of MI, stroke, death, or the end of the study period (January 1, 2002). The drug-gene interaction on the risk of MI or stroke was determined with a Cox proportional hazard model with adjustments for each drug class as time-dependent covariates. The risk of MI was increased in current use of ACE-inhibitors with the MT or TT genotype compared to ACE-inhibitors with the MM genotype (Synergy Index (SI): 4.00; 95% CI: 1.32-12.11). A significant drug-gene interaction was not found on the risk of stroke (SI: 1.83; 95% CI: 0.95-3.54) in ACE-inhibitor users or between current use of beta-blockers and the AGT M235T polymorphism on the risk of MI or stroke. ACE-inhibitor users with at least one copy of the 235T-allele of the AGT gene might have an increased risk of MI and stroke.
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PMID:Angiotensinogen M235T polymorphism and the risk of myocardial infarction and stroke among hypertensive patients on ACE-inhibitors or beta-blockers. 1729 37

The products of the renin-angiotensin system (RAS) play an important role in the pathogenesis of cardiovascular disease. Studies examining RAS gene variants and cardiovascular disease have focused on single-nucleotide polymorphisms (SNPs) rather than haplotypes, which better characterize the patterns of genetic variation. The authors conducted a population-based, case-control study at Group Health (Seattle, Washington) between 1995 and 1999 to determine whether common haplotypes in the angiotensinogen gene (AGT), the renin gene, the angiotensin-converting enzyme gene, and the angiotensin II receptor type 1 and receptor type 2 genes were associated with the risk of myocardial infarction and stroke among pharmacologically treated hypertensive patients. SNP discovery was done using 23 European-origin samples. Thirty tagSNPs (the minimum sets of SNPs that capture most of the haplotype diversity within a block) were genotyped in cases and controls. Haplotypes were inferred using the program PHASE (http://www.stat.washington.edu/stephens/software.html). The authors used weighted logistic regression to estimate associations and conducted a permutation test to estimate the probability of a chance finding. AGT haplotype B was associated with the risk of myocardial infarction (odds ratio = 1.58, 95% confidence interval: 1.06, 2.35); however, results were not statistically significant given the number of tests performed (permutation p = 0.17). In this case-control study, RAS gene haplotypes were not significantly associated with increased risks of myocardial infarction or stroke.
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PMID:Renin-angiotensin system haplotypes and the risk of myocardial infarction and stroke in pharmacologically treated hypertensive patients. 1752 61

Observational studies have documented an association between lower rates of cardiovascular disease and hormone therapy (HT). Meanwhile, randomized clinical trials have documented increased rates of myocardial infarction and stroke in women receiving hormone therapy. These seemingly discordant findings have stimulated new research to examine estrogen's effects on the cardiovascular system, including its effects on blood pressure, regulation of the renin-angiotensin system (RAS), and the clinical consequences of hypertension. In the last 6 years several studies have better defined the mechanisms by which HT affect the RAS, blood pressure, and the clinical effects of hypertension. Recent studies documented increases in angiotensinogen synthesis and the suppression of active renin with estrogen replacement. Genotype may be a factor in determining the degree of suppression of angiotensin converting enzyme levels that occurs with estrogen therapy. Estrogen supplementation in postmenopausal women increases systemic angiotensin II, a potent vasoconstrictor. This vasopressor effect is attenuated by an estrogen-induced reduction of angiotensin II type 1 receptor expression. Renal blood flow reduction, in the absence of blood pressure changes, have been reported after estrogen replacement, and an increased risk of total stroke has been demonstrated in hypertensive women on HT compared to normotensive women on this therapy. Estrogen replacement affects many components of the RAS, but its effect on this system has little effect on blood pressure. Further studies are needed to describe the effects of estrogen replacement on abnormal vasculature and how these effects relate to myocardial infarction and stroke.
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PMID:Effects of hormone therapy on blood pressure and the renin-angiotensin system in postmenopausal women. 1765 23

While gene polymorphism for angiotensinogen (AGT) is reported to contribute to the regulation of blood pressure and salt sensitivity, its effect on the risk of ischemic stroke remains controversial. We hypothesized that polymorphism of the AGT gene could be a risk factor for ischemic stroke. Major clinical risk factors and the AGT gene M235T polymorphism were examined in 147 consecutive stroke patients and 133 healthy age-matched controls. All patients were categorized into four stroke types (single lacuna, multiple lacunae, large-artery atherosclerosis and branch atheromatous disease in brainstem) and two vascular groups (large and perforating arterial lesions). The AGT gene M allele significantly increased the risk of single lacuna, multiple lacunae and small arterial lesions, in male patients (p=0.029, 0.031 and 0.026, respectively). Synergistic effects of the AGT gene polymorphism and clinical risks were not observed. In conclusion, AGT M allele may present a risk of lacunar infarctions in Japanese men, independent of hypertension.
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PMID:Angiotensinogen gene polymorphism as a risk factor for ischemic stroke. 1768 84

This study was designed to determine the effect of all-trans retinoic acid (RA) on the development of cardiac remodeling in a pressure overload rat model. Male Sprague-Dawley rats were subjected to sham operation and the aortic constriction procedure. A subgroup of sham control and aortic constricted rats were treated with RA for 5 mo after surgery. Pressure-overloaded rats showed significantly increased interstitial and perivascular fibrosis, heart weight-to-body weight ratio, and gene expression of atrial natriuretic peptide and brain natriuretic peptide. Echocardiographic analysis showed that pressure overload induced systolic and diastolic dysfunction, as evidenced by decreased fractional shortening, ejection fraction, stroke volume, and increased E-to-E(a) ratio and isovolumic relaxation time. RA treatment prevented the above changes in cardiac structure and function and hypertrophic gene expression in pressure-overloaded rats. RA restored the ratio of Bcl-2 to Bax, inhibited cleavage of caspase-3 and -9, and prevented the decreases in the levels of SOD-1 and SOD-2. Pressure overload-induced phosphorylation of ERK1/2, JNK, and p38 was inhibited by RA, via upregulation of mitogen-activated protein kinase phosphatase (MKP)-1 and MKP-2. The pressure overload-induced production of angiotensin II was inhibited by RA via upregulation of expression of angiotensin-converting enzyme (ACE)2 and through inhibition of the expression of cardiac and renal renin, angiotensinogen, ACE, and angiotensin type 1 receptor. Similar results were observed in cultured neonatal cardiomyocytes in response to static stretch. These results demonstrate that RA has a significant inhibitory effect on pressure overload-induced cardiac remodeling, through inhibition of the expression of renin-angiotensin system components.
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PMID:All-trans retinoic acid prevents development of cardiac remodeling in aortic banded rats by inhibiting the renin-angiotensin system. 1817 13

A brain renin angiotensin system (RAS) and its role in cardiovascular control and fluid homeostasis was at first controversial. This was because a circulating kidney-derived renin angiotensin system was so similar and well established. But, the pursuit of brain RAS has proven to be correct. In the course of accepting brain RAS, high standards of proof attracted state of the art techniques in all the new developments of biology. Consequently, brain RAS is a robust concept that has enlightened neuroscience as well as cardiovascular physiology and is a model neuropeptide system. Molecular biology confirmed the components of brain RAS and their location in the brain. Transgenic mice and rats bearing renin and extra copies of angiotensinogen genes revealed the importance of brain RAS. Cre-lox delivery in vectors has enabled pinpoint gene deletion of brain RAS in discrete brain nuclei. The new concept of brain RAS includes ACE-2, Ang1-7, and prorenin and Mas receptors. Angiotensin II (ANG II) generated in the brain by brain renin has many neural effects. It activates behavioral effects by selective activation of ANG II receptor subtypes in different locations. It regulates sympathetic activity and baroreflexes and contributes to neurogenic hypertension. New findings implicate brain RAS in a much wider range of neural effects. We review brain RAS involvement in Alzheimer's disease, stroke memory, and learning alcoholism stress depression. There is growing evidence to consider developing treatment strategies for a variety of neurological disease states based on brain RAS.
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PMID:Brain renin angiotensin in disease. 1838 68

Hypertension is one of the major health care problems worldwide since it markedly increases the risk for development of heart disease, stroke, generalized vascular disease, and renal failure. The renin-angiotensin system (RAS) with its major end-product angiotensin II (Ang II) plays a fundamental role in blood pressure regulation through direct and indirect mechanisms. Pharmacologically, we can inhibit the RAS using angiotensin-converting enzyme inhibitors and AT1 receptor blocker. Inhibiting renin directly with a clinically useful drug eluded pharmacologists until recently. However, the once-daily, orally effective, small-molecule, direct renin inhibitor aliskiren has recently changed this state of affairs. Aliskiren, with its 40-h half-life and ideal pharmacokinetics, can now address angiotensin production directly at its rate-limiting step. A novel transgenic rat model outfitted with the human renin and angiotensinogen genes allowed the testing of aliskiren in an animal model. Preclinical data demonstrated that aliskiren prolonged survival, decreased cardiac hypertrophy and the inducibility of arrhythmias, proteinuria, and attenuated inflammation. All these features might result in improved target-organ damage. Studies in humans attest to an effective blood pressure-lowering action, a largely side effect-free profile, and the option of several combination therapies. Aliskiren is the first of a novel antihypertensive drug class. The preclinical data is very promising. Nevertheless, for the evaluation of its potency in humans, we have to wait for more clinical data.
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PMID:Aliskiren--mode of action and preclinical data. 1844 51

To investigate the role of brain angiotensin II (ANG II) in the pathogenesis of injury following ischemic stroke, mice overexpressing renin and angiotensinogen (R+A+) and their wild-type control animals (R-A-) were used for experimental ischemia studies. Focal brain ischemia was induced by middle cerebral artery occlusion (MCAO). The severity of ischemic injury was determined by measuring neurological deficits and histological damage at 24 and 48 h after MCAO, respectively. To exclude the influence of blood pressure and local collateral blood flow, brain slices were used for oxygen and glucose deprivation (OGD) studies. The severity of OGD-induced damage was determined by measuring indicators of tissue swelling and cell death, the intensity of the intrinsic optical signal (IOS), and the number of propidium iodide (PI) staining cells, respectively. Results showed 1) R+A+ mice showed higher neurological deficit score (3.8 +/- 0.5 and 2.5 +/- 0.3 for R+A+ and R-A-, respectively, P < 0.01) and larger infarct volume (22.2 +/- 1.6% and 14.1 +/- 1.2% for R+A+ and R-A-, respectively, P < 0.01); 2) The R+A+ brain slices showed more severe tissue swelling and cell death in the cortex (IOS: 140 +/- 6% and 114 +/- 10%; PI: 139 +/- 20 cells/field and 39 +/- 9 cells/field for R+A+ and R-A-, respectively, P < 0.01); 3) treatment with losartan (20 micromol/l) abolished OGD-induced exaggeration of cell injury seen in R+A+ mice. The data indicate that activation of ANG II/AT(1) signaling is harmful to brain exposed to ischemia.
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PMID:Ischemia-induced brain damage is enhanced in human renin and angiotensinogen double-transgenic mice. 1975 35


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