Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the study was to analyze changes in myocardial angiotensinogen gene expression and myocardial angiotensin converting enzyme activity in slowly progressing low-output failure. In adult, male Wistar rats, acute ventricular tachypacing by 610 to 620 impulses per minute lowered end-diastolic external diameter of the left ventricle by 2.6% (p less than 0.01), but did not lower cardiac output or abolish coronary reserve, since left-ventricular subendocardial blood flow of paced rats increased under dipyridamole (2 mg/kg i.v.) by 56% (p less than 0.01). Systemic neuroendocrine activation and ventricular dilation without enlargement of ventricular mass developed subsequent to chronic tachypacing, but left-ventricular diameter during pacing never exceeded the value of sham rats on sinus rhythm. After 2 weeks, cardiac output was lowered by 14% (p less than 0.001), cardiopulmonary blood volume was elevated by 30% (p less than 0.001), and angiotensinogen mRNA and angiotensin converting enzyme activity in ventricular myocardium were doubled. We conclude that conditions for an enhanced intracardiac angiotensin II-formation developed in tachypacing-induced heart failure, but that enhanced systolic wall stress or myocardial ischemia are not required for this activation of the local cardiac renin-angiotensin system.
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PMID:Enhanced cardiac angiotensinogen gene expression and angiotensin converting enzyme activity in tachypacing-induced heart failure in rats. 165 3

Expression of the genes for renin and angiotensinogen has been documented in the heart and brain of several species, including rodents and primates. In the same tissues, local generation of angiotensin II has also been demonstrated. Neuropeptidergic brain angiotensin and local cardiac angiotensin participate in cardiovascular regulation. Inhibition of cardiac angiotensin II protects against deleterious arrythmogenic and metabolic effects of transient regional myocardial ischemia, and blockade of brain angiotensin II effectively lowers blood pressure in spontaneously hypertensive rats. It is surmised therefore that the therapeutic effects of converting enzyme inhibitors are, in part, brought about by inhibition of local tissue angiotensin II generation in addition to their interference with the hormonal plasma renin-angiotensin system. This would help to explain their therapeutic efficacy in pathophysiologic conditions in which hypertension is associated with low plasma renin activity.
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PMID:Endogenous tissue renin-angiotensin systems. From molecular biology to therapy. 306 97

The emerging recognition of the existence and potential biological significance of local tissue renin-angiotensin systems in a number of organs has fostered interest in a possible intrinsic cardiac renin-angiotensin system. Evidence for such a system was first provided by biochemical measurements of components of the renin-angiotensin system in cardiac tissue. It has recently been demonstrated that the genes coding for renin and angiotensinogen are expressed in all regions of the heart, an essential prerequisite for the postulated intracardiac biosynthesis of these proteins. Moreover, we have shown the presence of a functional and physiologically active pathway for the conversion of angiotensin I to angiotensin II in the beating mammalian heart. This conversion appears to be catalyzed by a specific cardiac converting enzyme that is susceptible to systemically administered converting-enzyme inhibitors. Evidence for the physiologic importance of the cardiac renin-angiotensin system comes from experimental data as well as indirect clinical evidence. The potent coronary vasoconstrictor properties of angiotensin II underscore its possible significance in myocardial ischemia and ischemic heart disease, in particular when viewed in the context of selective local activation. The long-known positive inotropic effects of angiotensin II are based on its direct myotropic properties and on its facilitatory effects on sympathetic neurotransmission and may be of added significance in metabolically compromised states. We have recently demonstrated that locally generated angiotensin may be a dominant etiologic factor in the pathogenesis of reperfusion arrhythmias. In addition, we have found experimental evidence for a deleterious effect of angiotensin II on myocardial metabolism in the setting of regional myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intracardiac generation of angiotensin and its physiologic role. 328 43

Myocardial infarction and stroke are the major cause of death in developed countries and are the clinical manifestation of atherosclerosis and hypertension. Both the environmental factors and genetic predisposition have an influence on the pathogenesis of these diseases. Despite we know lots of environmental risk factors and we made important advances in the prevention and treatment of mentioned diseases, our knowledge about the pathogenic linkage between genetic predisposition and cardiovascular diseases is still very little. Activation of the renin-angiotensin system has been proposed as a very important step in the pathogenesis of hypertension and atherosclerosis. In spite of vasoconstrictor activity, angiotensin II can stimulate migration and proliferation of vascular smooth muscle cells, macrophage-foam cells formation, adhesion and aggregation of platelets and fibrinolytic system inhibition. Angiotensin convertin enzyme inhibitors reduce the development of the atherosclerotic process after vascular injury and in hyperlipidemic animals. Blockade of renin-angiotensin system seems to be also effective in secondary prevention of myocardial infarction in men. In sum, the genetic variations inside the renin-angiotensin system which may affect the function of its components might have an influence on genetic predisposition to cardiovascular diseases. The paper deals with the current state of knowledge on association between polymorphic variations in renin gene, angiotensinogen gene, angiotensin converting enzyme gene and AT1 receptor gene and primary hypertension, ischaemic heart disease and myocardial infarction.
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PMID:[The role of DNA polymorphism in the renin-angiotensin system and the pathogenesis of cardiovascular diseases]. 923 64

The homozygous deletion allele of the angiotensin converting enzyme gene (ACE/DD), homozygous threonine allele of the angiotensinogen gene (AGN/TT), and the epsilon4 allele of the apolipoprotein E gene (apoE/epsilon4) are reported to be associated with ischemic heart disease. Cerebrovascular disease (CVD) is another atherosclerotic disease; and the effects of these polymorphisms on CVD have been confusing. In this study, we investigated whether ACE/DD, AGN/TT, and apoE/epsilon4 genotypes are associated with CVD and whether genetic risk is enhanced by the effect of one upon another. We ascertained these genotypes in patients with cerebral infarction (n = 55) and cerebral hemorrhage (n = 38), diagnosed by brain computed tomography. Control subjects for the infarction group and the hemorrhage group were randomly selected from 583 subjects matched for age, gender, and history of hypertension with patients. Frequency of ACE/DD genotype was higher in the patients with infarction than in the controls (chi2 = 6.1, P < .05). The AGN/TT genotype was not associated with either infarction or hemorrhage, but it increased the relative risk for cerebral infarction in the subjects with ACE/DD genotype (chi2 = 8.0, P < .01, odds ratio; 11.7, 95% confidence intervals: 1.4 to 96.0). There was no significant association between apoE/epsilon4 and CVD. These results suggest that ACE/DD predicts cerebral infarction, but not cerebral hemorrhage, and that AGN/TT enhances the risk for cerebral infarction associated with ACE/DD.
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PMID:Polymorphism of angiotensin converting enzyme, angiotensinogen, and apolipoprotein E genes in a Japanese population with cerebrovascular disease. 944 75

This review introduces recent progress in molecular genetics of cardiovascular diseases. Many genes and their mutations causing familial cardiovascular diseases have been discovered, including familial hypertrophic cardiomyopathy which is caused by mutated cardiac beta myosin heavy chain, light chains, troponin T, troponin I, or alpha-tropomyosin, and long QT syndrome by KvLQT1, HERG, minK or cardiac voltage-dependent Na channel mutation. The mutations in causative genes can affect clinical courses of diseases; amino acid substitutions of cardiac beta myosin heavy chain with charge changes seem to cause poorer prognosis of hypertrophic cardiomyopathy. Besides monogenic diseases, there are many cardiovascular diseases affected with genetic polymorphisms, such as hypertension, ischemic heart disease and atherosclerosis. Specific amino acid mutations or polymorphisms in the promoter region of the genes are known to become a risk factor of these diseases. Polymorphisms of genes encoding apolipoprotein E, angiotensin converting enzyme, angiotensinogen and endothelial NO synthase (ecNOS) have been well characterized as an important risk factor of cardiovascular diseases. We recently found a novel gene which seems to affect human aging phenotype and vascular endothelial function. It is important as a future study to clarify the regulatory mechanisms of the klotho gene in the cardiovascular system and the clinical significance of klotho gene polymorphisms.
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PMID:[Molecular genetics of cardiovascular diseases]. 956 64

To date, the human angiotensinogen (AGT) gene and some of its variants represent the best examples of genetic influences that are involved in the determination of essential hypertension (EH) and associated cardiovascular diseases (CVDs). To assess the value of genotyping AGT in a genetically homogeneous population, we carried out a retrospective, case control study of variants M235T and T174M for putative correlations with CVDs among nationals from the United Arab Emirates (Emirati)--an ethnic group characterized by no alcohol intake and no cigarette smoking. We investigated a sample population of 229 Emirati (119 males and 110 females), comprising groups of controls and patients with clinical diagnoses of EH, left ventricular hypertrophy (LVH), ischaemic heart disease (IHD) and myocardial infarction (MI). M235T and T174M alleles were determined via assays based on the polymerase chain reaction. T174M showed no correlation with any of the four clinical entities included in this study. T235 alleles, however, occurred more frequently in the EH group and less frequently in the group of MI survivors. We also found that T235 allele frequencies decreased with age, indicating that in the Emirati population, T235 alleles are associated with a reduced life span and that this effect could occur through independent mechanisms underlying genetic susceptibilities to both EH and MI.
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PMID:Associations of angiotensinogen gene mutations with hypertension and myocardial infarction in a gulf population. 983 39

We recently reported that in the ischemic human heart, locally formed angiotensin II activates angiotensin II type 1 (AT(1)) receptors on sympathetic nerve terminals, promoting reversal of the norepinephrine transporter in an outward direction (i.e., carrier-mediated norepinephrine release). The purpose of this study was to assess whether cardiac sympathetic nerve endings contribute to local angiotensin II formation, in addition to being a target of angiotensin II. To this end, we isolated sympathetic nerve endings (cardiac synaptosomes) from surgical specimens of human right atrium and incubated them in ischemic conditions (95% N(2,) sodium dithionite, and no glucose for 70 min). These synaptosomes released large amounts of endogenous norepinephrine via a carrier-mediated mechanism, as evidenced by the inhibitory effect of desipramine on this process. Norepinephrine release was further enhanced by preincubation of synaptosomes with angiotensinogen and was prevented by two renin inhibitors, pepstatin-A and BILA 2157BS, as well as by the angiotensin-converting enzyme inhibitor enalaprilat and the AT(1) receptor antagonist EXP 3174 [2-N-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl] methyl]imidazole-5-carboxylic acid]. Western blot analysis revealed the presence of renin in cardiac sympathetic nerve terminals; renin abundance increased ~3-fold during ischemia. Thus, renin is rapidly activated during ischemia in cardiac sympathetic nerve terminals, and this process eventually culminates in angiotensin II formation, stimulation of AT(1) receptors, and carrier-mediated norepinephrine release. Our findings uncover a novel autocrine/paracrine mechanism whereby angiotensin II, formed at adrenergic nerve endings in myocardial ischemia, elicits carrier-mediated norepinephrine release by activating adjacent AT(1) receptors.
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PMID:Ischemia promotes renin activation and angiotensin formation in sympathetic nerve terminals isolated from the human heart: contribution to carrier-mediated norepinephrine release. 1213 Jul 13

It is now well established that vascular inflammation is an independent risk factor for the development of atherosclerosis. In otherwise healthy patients, chronic elevations of circulating interleukin-6 or its biomarkers are predictors for increased risk in the development and progression of ischemic heart disease. Although multifactorial in etiology, vascular inflammation produces atherosclerosis by the continuous recruitment of circulating monocytes into the vessel wall and by contributing to an oxidant-rich inflammatory milieu that induces phenotypic changes in resident (noninflammatory) cells. In addition, the renin-angiotensin system (RAS) has important modulatory activities in the atherogenic process. Recent work has shown that angiotensin II (Ang II) has significant proinflammatory actions in the vascular wall, inducing the production of reactive oxygen species, inflammatory cytokines, and adhesion molecules. These latter effects on gene expression are mediated, at least in part, through the cytoplasmic nuclear factor-kappaB transcription factor. Through these actions, Ang II augments vascular inflammation, induces endothelial dysfunction, and, in so doing, enhances the atherogenic process. Our recent studies have defined a molecular mechanism for a biological positive-feedback loop that explains how vascular inflammation can be self-sustaining through upregulation of the vessel wall Ang II tone. Ang II produced locally by the inflamed vessel induces the synthesis and secretion of interleukin-6, a cytokine that induces synthesis of angiotensinogen in the liver through a janus kinase (JAK)/signal transducer and activator of transcription (STAT)-3 pathway. Enhanced angiotensinogen production, in turn, supplies more substrate to the activated vascular RAS, where locally produced Ang II synergizes with oxidized lipid to perpetuate atherosclerotic vascular inflammation. These observations suggest that one mechanism by which RAS antagonists prevent atherosclerosis is by reducing vascular inflammation. Moreover, antagonizing the vascular nuclear factor-kappaB and/or hepatic JAK/STAT pathways may modulate the atherosclerotic process.
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PMID:Vascular inflammation and the renin-angiotensin system. 1217 84

In this study of 10 690 individuals, associations with elevated blood pressure, ischemic heart disease, and ischemic cerebrovascular disease were determined for two noncoding [A(-20)C, G(-6)A] and two coding (T174M, M235T) single nucleotide polymorphisms, analyzed alone and in combination (haplotypes). Participants from the general population with (n=4950) and without (n=4234) elevated blood pressure were compared (study 1), as were participants from the general population without ischemic heart disease and ischemic cerebrovascular disease (n=7965) and cases with either ischemic heart disease (n=1850, study 2) or ischemic cerebrovascular disease (n=848, study 3). Finally, 22-year follow-up of 9184 individuals from the general population examined risk of ischemic heart disease (study 4) and ischemic cerebrovascular disease (study 5). Individuals with -6AA, 174TT, or 235TT had plasma angiotensinogen levels increased by 80 ng/mL (P=0.01 and 0.05 for women and men) compared with individuals with -6GG, 174TT, or 235 MM. In women, this difference was associated with an odds ratio of elevated blood pressure of 1.25 (1.03 to 1.51), which increased to 1.63 (1.05 to 2.51) in postmenopausal women receiving hormone replacement therapy. The promoter single nucleotide polymorphisms alone or as haplotypes did not predict the continuous variables of systolic, diastolic, or pulse pressure in cross section or the risk of ischemic heart disease or ischemic cerebrovascular disease in either gender in case-control or prospective studies. Individuals with -6AA, 174TT, or 235TT in the angiotensinogen gene have increased plasma angiotensinogen levels and moderately increased risk of elevated blood pressure (women only) but unaltered blood pressure examined as a continuous variable and unaltered risk of ischemic heart disease and ischemic cerebrovascular disease.
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PMID:Angiotensinogen single nucleotide polymorphisms, elevated blood pressure, and risk of cardiovascular disease. 1274 9


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