angiotensinogen and Myocardial-Ischemia

The aim of this study was to investigate whether the M235T polymorphism in the angiotensinogen gene was associated with angiotensinogen levels, systolic and diastolic blood pressure, hypertension, and risk of ischemic cardiovascular disease in different ethnic populations.. One hundred twenty-seven studies published between January 1992 and March 2002 examining the association of angiotensinogen gene polymorphisms with the above-mentioned end points were selected. Pooled effect sizes and Mantel-Haenszel odds ratios were calculated using Review Manager. In white subjects, genotype was associated with a stepwise increase in plasma angiotensinogen levels of 5% (95% CI, 2% to 8%; P=0.0004) in MT heterozygotes and 11% (7% to 15%; P<0.00001) in TT homozygotes compared with MM individuals. Correspondingly, genotype was associated with a stepwise increase in aggregated odds ratio for hypertension of 1.08 (95% CI, 1.01 to 1.15) in MT individuals and 1.19 (1.10 to 1.30) in TT individuals in white subjects and of 1.29 (95% CI, 0.96 to 1.74) and 1.60 (1.19 to 2.15) in Asian subjects. M235T genotype did not predict systolic or diastolic blood pressure or risk of ischemic heart disease or myocardial infarction in either ethnic group.. Angiotensinogen M235T genotype was associated with a stepwise increase in angiotensinogen levels in white subjects and a corresponding increase in risk of hypertension in both white and Asian subjects.

Topics: Angiotensinogen; Asian People; Black People; Blood Pressure; Genotype; Heterozygote; Homozygote; Humans; Hypertension; Myocardial Infarction; Myocardial Ischemia; Polymorphism, Genetic; Stroke; White People

Recent studies have shown that the JAK-STAT signaling pathway plays a central role in cardiac pathophysiology. JAK-STAT signaling has been implicated in pressure overload-induced cardiac hypertrophy and remodeling, ischemic preconditioning, and ischemia/reperfusion-induced cardiac dysfunction. The different STAT family members expressed in cardiac myocytes appear to be linked to different, and at times, opposite responses, such as cell growth/survival and apoptosis. Thus, differential activation and/or selective inhibition of the STAT proteins by agonists for G-protein coupled receptors, such as angiotensin II, may contribute to cardiac dysfunction during ischemia and heart failure. In addition, JAK-STAT signaling may represent one limb of an autocrine loop for angiotensin II generation, that serves to amplify the actions of angiotensin II on cardiac muscle. The purpose of this article is to provide an overview of recent findings that have been made for JAK-STAT signaling in cardiac myocytes and to highlight some unresolved issues for future investigation. The central focus of this review is on recent studies suggesting that modulation or activation of JAK-STAT signaling by ANG II has pathological consequences for heart function.

Topics: Angiotensinogen; Apoptosis; Autocrine Communication; Cardiomegaly; Cytokines; DNA-Binding Proteins; Heart; Heart Diseases; Heart Failure; Janus Kinase 1; Janus Kinase 2; MAP Kinase Signaling System; Milk Proteins; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Protein-Tyrosine Kinases; Proteins; Proto-Oncogene Proteins; Renin-Angiotensin System; Signal Transduction; STAT1 Transcription Factor; STAT3 Transcription Factor; STAT5 Transcription Factor; STAT6 Transcription Factor; Trans-Activators; TYK2 Kinase

Polymorphism of the (CA)n repetitive sequence in the angiotensinogen gene was studied in a random sample of Russian males from the Moscow population and in a sample of patients with coronary heart disease. Thirteen allelic variants of this microsatellite with 10 to 22 (CA) dinucleotides were revealed. In the patients, the spectrum of the allelic variants of the angiotensinogen gene tended to shift toward smaller numbers of repeats (n < or = 16). This shift was not associated with changes in the lipid composition of blood.

Topics: Adult; Alleles; Angiotensinogen; Gene Frequency; Heterozygote; Humans; Lipids; Male; Microsatellite Repeats; Middle Aged; Moscow; Myocardial Ischemia; Polymorphism, Genetic

Heart chymase rather than angiotensin (Ang)-converting enzyme has higher specificity for Ang I conversion into Ang II in humans. A new pathway for direct cardiac Ang II generation has been revealed through the demonstration that Ang-(1-12) is cleaved by chymase to generate Ang II directly. Herein, we address whether Ang-(1-12), chymase messenger RNA (mRNA), and activity levels can be differentiated in human atrial tissue from normal and diseased hearts and if these measures associate with various pathologic heart conditions.. Atrial appendages were collected from 11 nonfailing donor hearts and 111 patients undergoing heart surgery for the correction of valvular heart disease, resistant atrial fibrillation, or ischemic heart disease. Chymase mRNA was analyzed by real-time polymerase chain reaction and enzymatic activity by high-performance liquid chromatography using Ang-(1-12) as the substrate. Ang-(1-12) levels were determined by immunohistochemical staining.. Chymase gene transcripts, chymase activity, and immunoreactive Ang-(1-12) expression levels were higher in left atrial tissue compared with right atrial tissue, irrespective of cardiac disease. In addition, left atrial chymase mRNA expression was significantly higher in stroke versus nonstroke patients and in cardiac surgery patients who had a history of postoperative atrial fibrillation versus nonatrial fibrillation. Correlation analysis showed that left atrial chymase mRNA was positively related to left atrial enlargement, as determined by echocardiography.. As Ang-(1-12) expression and chymase gene transcripts and enzymatic activity levels were positively linked to left atrial size in patients with left ventricular heart disease, an important alternate Ang II forming pathway, via Ang-(1-12) and chymase, in maladaptive atrial and ventricular remodeling in humans is uncovered.

Topics: Aged; Angiotensinogen; Animals; Atrial Fibrillation; Chymases; Echocardiography; Female; Gene Expression Profiling; Heart Atria; Heart Valve Diseases; Heart Ventricles; Humans; Immunohistochemistry; Male; Middle Aged; Myocardial Ischemia; Peptide Fragments; RNA, Messenger; Stroke; Ventricular Remodeling

In the heart, secretory renin promotes hypertrophy, apoptosis, necrosis, fibrosis, and cardiac failure through angiotensin generation from angiotensinogen. Thus, inhibitors of the renin-angiotensin system are among the most potent drugs in the treatment of cardiac failure. Renin transcripts have been identified encoding a renin isoform with unknown targets and unknown functions that are localized to the cytosol and mitochondria. We hypothesize that this isoform, in contrast to secretory renin, exerts cardioprotective effects in an angiotensin-independent manner. Cells overexpressing cytosolic renin were generated by transfection or obtained from CX(exon2-9)renin transgenic rats. Overexpression of cytosolic renin reduced the rate of necrosis in H9c2 cardiomyoblasts and in primary cardiomyocytes after glucose depletion. These effects were not mediated by angiotensin generation since an inhibitor of renin activity did not influence the in vitro effects. siRNA-mediated knockdown of endogenous cytosolic renin increased the rate of necrosis and aggravated the pro-necrotic effects of glucose depletion. Isolated perfused hearts obtained from transgenic rats overexpressing cytosolic renin exhibited a 50% reduction of infarct size after ischemia-reperfusion injury. Cytosolic renin is essential for survival, both under basal conditions and during glucose starvation. The protective effects are angiotensin-independent and contrary to the known actions of secretory renin.. A cytosolic isoform of renin with unknown functions is expressed in the heart. Cytosolic renin diminishes ischemia induced damage to the heart. The protective effects of cytosolic renin contradict the known function of secretory renin. The effects of cytosolic renin are not mediated via angiotensin generation. Renin-binding protein is a potential target for cytosolic renin.

Topics: Angiotensinogen; Animals; Cardiotonic Agents; Cells, Cultured; Cytosol; Glucose; Heart; Myocardial Ischemia; Myocytes, Cardiac; Necrosis; Protein Isoforms; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Rats, Wistar; Renin; Renin-Angiotensin System; RNA Interference; RNA, Small Interfering

Heart chymase rather than angiotensin converting enzyme has higher specificity for angiotensin (Ang) I conversion into Ang II in humans. A new pathway for direct cardiac Ang II generation has been revealed through the demonstration that Ang-(1-12) is cleaved by chymase to generate Ang II directly. We address here whether Ang-(1-12) and chymase gene expression and activity are detected in the atrial appendages of 44 patients (10 females) undergoing heart surgery for the correction of valvular heart disease, resistant atrial fibrillation or ischemic heart disease.. Immunoreactive Ang-(1-12) expression was 54% higher in left atrial compared with right atrial appendages. This was associated with higher abundance of left atrial appendage chymase gene transcripts and chymase activity, but no differences in angiotensinogen mRNA. Atrial chymase enzymatic activity was highly correlated with left atrial but not right atrial enlargement as determined by echocardiography, while both tyrosine hydroxylase and neuropeptide Y atrial appendage mRNAs correlated with atrial angiotensinogen mRNAs.. Higher Ang-(1-12) expression and upregulation of chymase gene transcripts and enzymatic activity from the atrial appendages connected to the enlarged left versus right atrial chambers of subjects with left heart disease defines a role of this alternate Ang II forming pathway in the processes accompanying adverse atrial and ventricular remodeling.

Topics: Aged; Angiotensin I; Angiotensin II; Angiotensinogen; Atrial Fibrillation; Chymases; Echocardiography; Female; Gene Expression Regulation, Enzymologic; Heart Atria; Heart Valve Diseases; Humans; Male; Middle Aged; Myocardial Ischemia; RNA, Messenger; Up-Regulation; Ventricular Remodeling

Clinically and experimentally, a case for omega-3 polyunsaturated fatty acid (PUFA) cardioprotection in females has not been clearly established. The goal of this study was to investigate whether dietary omega-3 PUFA supplementation could provide ischemic protection in female mice with an underlying genetic predisposition to cardiac hypertrophy. Mature female transgenic mice (TG) with cardiac-specific overexpression of angiotensinogen that develop normotensive cardiac hypertrophy and littermate wild-type (WT) mice were fed a fish oil-derived diet (FO) or PUFA-matched control diet (CTR) for 4 wk. Myocardial membrane lipids, ex vivo cardiac performance (intraventricular balloon) after global no-flow ischemia and reperfusion (15/30 min), and reperfusion arrhythmia incidence were assessed. FO diet suppressed cardiac growth by 5% and 10% in WT and TG, respectively (P < 0.001). The extent of mechanical recovery [rate-pressure product (RPP) = beats/min x mmHg] of FO-fed WT and TG hearts was similar (50 +/- 7% vs. 45 +/- 12%, 30 min reperfusion), and this was not significantly different from CTR-fed WT or TG. To evaluate whether systemic estrogen was masking a protective effect of the FO diet, the responses of ovariectomized (OVX) WT and TG mice to FO dietary intervention were assessed. The extent of mechanical recovery of FO-fed OVX WT and TG (RPP, 50 +/- 4% vs. 64 +/- 8%) was not enhanced compared with CTR-fed mice (RPP, 60 +/- 11% vs. 80 +/- 8%, P = 0.335). Dietary FO did not suppress the incidence of reperfusion arrhythmias in WT or TG hearts (ovary-intact mice or OVX). Our findings indicate a lack of cardioprotective effect of dietary FO in females, determined by assessment of mechanical and arrhythmic activity postischemia in a murine ex vivo heart model.

Topics: Angiotensin II; Angiotensinogen; Animals; Arrhythmias, Cardiac; Dietary Fats, Unsaturated; Disease Models, Animal; Estrogens; Female; Fish Oils; Genetic Predisposition to Disease; Hypertrophy; Mice; Mice, Transgenic; Myocardial Ischemia; Myocardium; Ovariectomy; Reperfusion Injury

To examine the contribution of six cardiovascular polymorphisms to the occurrence of a first event of ischemic heart disease (IHD) in a primary care population with a high prevalence of hypertension. Furthermore, we specified the data for sex and age.. In this cross sectional case-control study, patients with a first event of IHD (157) and event-free controls (571) were studied. Both the groups were genotyped for the angiotensin II type 1 receptor (A1166C), angiotensinogen (M235 T), angiotensin converting enzyme (4656rpt), endothelial nitric oxide synthase (E298D), G-protein beta3 subunit (C825 T), and alpha-adducin (G460W) polymorphisms. Univariate and multivariate odds ratios (ORs) were calculated to assess the association between a first ischemic event and these polymorphisms. Sliding mean analyses were performed to show age-specific associations.. Multivariate ORs indicated a protective association for the carrier status of the T-allele of AGT, overall [OR = 0.69 (0.34-0.90)] and for males [OR = 0.58 (0.27-0.89)]. Sliding mean analyses showed a continuous protective association with IHD of the T-allele of AGT with increasing age in males, whereas in females an increased risk for IHD was observed with a maximum OR of 1.6 at the age of 56 years.. In this population the T-allele of the AGT polymorphism is protective for a first event of IHD in males.

Topics: Age Factors; Aged; Angiotensinogen; Calmodulin-Binding Proteins; Case-Control Studies; Cross-Sectional Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Heterotrimeric GTP-Binding Proteins; Humans; Hypertension; Logistic Models; Male; Middle Aged; Myocardial Ischemia; Nitric Oxide Synthase Type III; Odds Ratio; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Primary Health Care; Receptor, Angiotensin, Type 1; Risk Assessment; Risk Factors; Sex Factors

The influence of intracellular renin plus angiotensinogen (Ao) as well as angiotensin (Ang) II on cell volume was investigated in myocytes isolated from the heart of four-month-old cardiomyopathic hamsters (TO-2) and normal hamsters (F1B). Measurements of cell width and cell length were performed on quiescent cells using a Px-it imaging and computer system. The cell volume was calculated assuming the cells as elliptical cylinders and taking the cell depth equal to one third of cell width. For measurements of sodium pump current, the cells were voltage clamped (holding potential -40 mV) using the whole cell configuration. Cells were exposed to K-free solution to inhibit the pump and then to normal Krebs solution to reactivate the pump. In other experiments the cells were voltage clamped (holding potential -40 mV) and changes in the background current elicited by renin plus Ao or by Ang II were monitored. The results indicated that: a) intracellular dialysis of renin (128 pmol Ang I/ml) plus Ao (110 pmol Ang I generated by renin by exhaustion) decreased the cell volume concurrently with the activation of the sodium pump; b) intracellular losartan (10(-)8 M) or extracellular ouabain (10(-8) M) abolished the effect of renin plus Ao on cell volume; c) intracellular Ang II (10(-8) M), by itself, reduced cell volume and increased the pump current density; d) extracellular administration of renin plus Ao, at the same concentration used intracellularly, increased cell volume and inhibited the sodium pump. This increase of cell volume elicited by extracellular renin plus Ao was related to the activation of the Na-K-2Cl cotransporter; e) intracellular Ang II (10(-8) M) reversed cell swelling induced by hypotonic solutions.. Intracellular and extracellular renin plus Ao have opposite effects on sodium pump and cell volume regulation in the failing heart. Both effects of renin plus Ao are dependent upon the formation of Ang II. Since intracellular Ang II counteracted the cell swelling induced by hypotonic solution, it is reasonable to think that the activation of the intracrine renin-angiotensin system might play a protective role during myocardial ischaemia by reducing cell volume.

Topics: Angiotensin II; Angiotensinogen; Animals; Bumetanide; Cardiomyopathy, Dilated; Cardiotonic Agents; Cell Separation; Cell Size; Cricetinae; Diuretics; Extracellular Space; Hypotonic Solutions; Myocardial Ischemia; Myocytes, Cardiac; Ouabain; Patch-Clamp Techniques; Renin; Serine Proteinase Inhibitors; Sodium-Potassium-Exchanging ATPase

Although great progress has been made in reducing renarrowing of the lumen after stenting of coronary arteries, a considerable number of patients develop recurrent in-stent stenosis. Several studies suggest that neointimal proliferation is the crucial pathophysiological process underlying restenosis after stenting. The renin-angiotensin-aldosterone system (RAS) has been implicated in the development of neointimal hyperplasia. We tested the hypothesis that polymorphisms of the RAS genes are associated with recurrent in-stent restenosis (ISR). Coronary stent implantation was performed in 272 patients with clinical symptoms or objective signs of ischemia. At follow-up angiography 6 months after stenting, 81 patients (29.8%) revealed in-stent restenosis. These patients underwent balloon angioplasty and were scheduled for a further 6 months of follow up. One year after initial stenting of the coronary artery, 39 patients displayed no significant angiographic ISR, whereas 42 patients developed recurrent in-stent restenosis (RISR). The survey of specific functional polymorphisms of the RAS, namely the angiotensin-I converting enzyme (ACE) D/I, the angiotensinogen (AGT) T174M and M235T, and A1166C of the angiotensin-II receptor 1 (AGTR1), revealed that the incidence RISR in the high-risk cohort was not associated with any of the polymorphisms examined in this study.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Angiotensinogen; Cell Proliferation; Coronary Angiography; Coronary Restenosis; Diabetes Mellitus; Female; Gene Deletion; Human Growth Hormone; Humans; Male; Middle Aged; Myocardial Ischemia; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Recurrence; Renin-Angiotensin System; Stents

Topics: Angiotensin II; Angiotensinogen; Animals; Anti-Arrhythmia Agents; Buffers; Captopril; Diabetes Complications; Diabetes Mellitus, Experimental; Diffusion; Free Radical Scavengers; Imidazoles; Kallikreins; Mice; Mice, Transgenic; Myocardial Ischemia; Myocardium; Perfusion; Rats; Renin-Angiotensin System; Ribosomal Protein S6 Kinases, 90-kDa; Species Specificity; Tetrazoles

Polymorphism of the promoter region of the angiotensinogen gene (ATG) and an angiotensin I-converting enzyme gene (ACE) insertion/deletion (I/D) polymorphism were studied in three different groups of Kazakhs (control group, patients with cardiovascular disease (CAD) and patients with arterial hypertension (AH)) using three methods. A comparative analysis of the distribution of genotype and allele frequencies was conducted.

Topics: Angiotensinogen; Asian People; Ethnicity; Gene Frequency; Genetic Predisposition to Disease; Humans; Hypertension; Introns; Kazakhstan; Male; Middle Aged; Myocardial Ischemia; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Promoter Regions, Genetic; Sequence Deletion

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.

Topics: Angiotensinogen; Blood Pressure; Brain Ischemia; Case-Control Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Male; Middle Aged; Myocardial Ischemia; Polymorphism, Single Nucleotide; Prospective Studies

Topics: Angiotensinogen; Brain Ischemia; Case-Control Studies; Denmark; Female; Heterozygote; Homozygote; Humans; Male; Mutation; Myocardial Infarction; Myocardial Ischemia; Risk Factors

In 76 patients with heart failure (HF) (New York Heart Association [NYHA] classes I through IV) and in 15 control subjects, cardiac angiotensin II (Ang II) generation and its relationship with left ventricular function were investigated by measuring aorta-coronary sinus concentration gradients of endogenous angiotensins and in a part of patients by studying (125)I-labeled Ang I kinetics. Gene expression and cellular localization of the cardiac renin-angiotensin system components, the density of AT(1) and AT(2) on membranes and isolated myocytes, and the capacity of isolated myocytes for synthesizing the hypertrophying growth factors insulin-like growth factor-I (IGF-I) and endothelin (ET)-1 were also investigated on 22 HF explanted hearts (NYHA classes III and IV) and 7 nonfailing (NF) donor hearts. Ang II generation increased with progression of HF, and end-systolic wall stress was the only independent predictor of Ang II formation. Angiotensinogen and angiotensin-converting enzyme mRNA levels were elevated in HF hearts, whereas chymase levels were not, and mRNAs were almost exclusively expressed on nonmyocyte cells. Ang II was immunohistochemically detectable both on myocytes and interstitial cells. Binding studies showed that AT(1) density on failing myocytes did not differ from that of NF myocytes, with preserved AT(1)/AT(2) ratio. Conversely, AT(1) density was lower in failing membranes than in NF ones. Ang II induced IGF-I and ET-1 synthesis by isolated NF myocytes, whereas failing myocytes were unable to respond to Ang II stimulation. This study demonstrates that (1) the clinical course of HF is associated with progressive increase in cardiac Ang II formation, (2) AT(1) density does not change on failing myocytes, and (3) failing myocytes are unable to synthesize IGF-I and ET-1 in response to Ang II stimulation.

Topics: Analysis of Variance; Angiotensin I; Angiotensin II; Angiotensinogen; Cardiomyopathy, Dilated; Cardiovascular Diseases; Chymases; Endothelin-1; Gene Expression; Gene Expression Regulation; Heart Ventricles; Immunohistochemistry; In Situ Hybridization; Insulin-Like Growth Factor I; Iodine Radioisotopes; Myocardial Ischemia; Myocardium; Peptidyl-Dipeptidase A; Platelet-Derived Growth Factor; Protein Precursors; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; RNA, Messenger; Serine Endopeptidases; Ventricular Function, Left

The M235T and T174M angiotensinogen mutations have been linked to increased risk for ischemic heart and cerebrovascular disease.. To determine whether angiotensinogen mutations are associated with ischemic heart disease, myocardial infarction, and ischemic cerebrovascular disease.. Six case-control studies from the Copenhagen City Heart Study.. Copenhagen, Denmark.. Participants in the Copenhagen City Heart Study and patients from the same hospital with ischemic heart disease (n = 866 and n = 943, respectively), myocardial infarction (n = 519 and n = 493, respectively), or ischemic cerebrovascular disease (n = 489 and n = 434, respectively) and 7975 controls without these conditions.. Genotypes for the M235T and T174M angiotensinogen mutations were compared between controls and Copenhagen City Heart Study participants with ischemic heart disease, myocardial infarction, and cerebrovascular disease (studies 1a, 1b, and 1c) and patients from Copenhagen University Hospital with the same conditions (studies 2a, 2b, and 2c).. Relative allele frequencies of 235T and 174M in the general population were 0.41 and 0.12, respectively. Genotype was not associated with increased risk for ischemic heart or ischemic cerebrovascular disease in studies of either mutation alone or combined in women or men. Among compound heterozygotes (235MT /174TM ), women in case-control study 2a had decreased risk for ischemic heart disease in age-adjusted analysis; however, this decreased risk was not seen in multifactorial-adjusted or matched analyses, in men, or in case-control study 1a. Among double homozygotes (235TT /174MM ), women in case-control study 2b had increased risk for myocardial infarction in matched analysis; however, this increased risk was not seen in age- or multifactorial-adjusted analyses, in men, or in case-control study 1b. Among single homozygotes (235TT /174TT ), men in case-control study 2b had increased risk for myocardial infarction in multifactorial-adjusted and matched analyses. This risk was not present in age-adjusted analysis, in women, or in case-control study 1b. In addition, male single homozygotes had decreased risk for ischemic cerebrovascular disease in case-control study 2c in age- and multifactorial-adjusted analyses, but this finding was not seen in matched analysis, in women, or in case-control study 1c.. In six large case-control studies, the M235T and T174M angiotensinogen mutations were not consistently associated with increased (or decreased) risk for ischemic heart disease, myocardial infarction, or ischemic cerebrovascular disease. Statistically significant associations may represent chance findings rather than real phenomena.

Topics: Aged; Angiotensinogen; Brain Ischemia; Case-Control Studies; Female; Genetic Predisposition to Disease; Heterozygote; Homozygote; Humans; Male; Middle Aged; Mutation; Myocardial Infarction; Myocardial Ischemia; Regression Analysis; Risk Factors

Topics: Angiotensinogen; Brain Ischemia; Genetic Predisposition to Disease; Humans; Mutation; Myocardial Infarction; Myocardial Ischemia; Risk Factors

Activation of the heart renin-angiotensin system (RAS) under pathophysiological conditions has been correlated with the development of ischemic injury. The binding of angiotensin II to its receptors triggers induction of several, perhaps multifunctional, intracellular signaling pathways, notable among them the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. In this study, we investigated whether the JAK/STAT signaling is involved in the ischemia/reperfusion injury in adult rat myocardium.. We report here that 2 components of the JAK/STAT signaling pathway, namely STAT 5A and STAT 6, are selectively activated in the rat heart subjected to ischemia/reperfusion. The activated STATs bind to a conserved nucleotide sequence (St domain) in the promoter of the angiotensinogen (ANG) gene and consequently upregulate the level of ANG mRNA. Treatment of the hearts with losartan (4.5 micromol/L), an AT(1) blocker, or with tyrphostin AG490 (5 micromol/L), an inhibitor of JAK 2 phosphorylation, results in loss of the STAT/ANG promoter binding activity and an upregulated level of ANG mRNA. Hearts treated with the JAK 2 inhibitor tyrphostin AG490 showed a reduction in myocardial infarct size and in number of cardiomyocytes undergoing apoptosis. The treated hearts also showed a recovery in functional hemodynamics of the myocardium.. These findings suggest that activation of the JAK/STAT signaling pathway is a significant contributing factor to the pathogenesis of myocardial ischemia and that interference in activation of the pathway potentiates recovery in cardiac function.

Topics: Angiotensinogen; Animals; DNA-Binding Proteins; Enzyme Inhibitors; In Vitro Techniques; Janus Kinase 2; Male; Milk Proteins; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Phosphorylation; Promoter Regions, Genetic; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Rats; RNA, Messenger; Signal Transduction; STAT5 Transcription Factor; STAT6 Transcription Factor; Trans-Activators; Tyrphostins; Up-Regulation

In a hospital cohort study, we examined whether or not ACE (Angiotensin-I converting enzyme) and AGT (Angiotensinogen) gene polymorphisms were associated with the development of nephropathy in long-term Japanese insulin-dependent diabetes mellitus (IDDM) patients with or without proliferative retinopathy, and whether or not the polymorphisms were associated with an arteriosclerotic family history in first degree relatives of the patients. A total of 201 patients with IDDM for more than 10 years and 159 patients with IDDM for more than 15 years were randomly selected in our hospital. All patients received uniform diabetes management and were divided into three groups, no nephropathy, incipient nephropathy and clinical nephropathy groups. There were no differences in clinical characteristics excluding urinary albumin to creatinine ratio and systolic blood pressure between the three groups. ACE I/D polymorphism was related to plasma ACE activity, but there were no associations between ACE I/D polymorphism and the development of diabetic nephropathy, nor was renal deterioration observed in patients with proliferative retinopathy even in those with a history of diabetes for more than 15 years. The AGT polymorphism did not have an additive effect on the association between ACE polymorphism and the development of diabetic nephropathy in patients with or without retinopathy. Development of diabetic nephropathy in the patients with or without proliferative retinopathy did not result in ACE or AGT polymorphisms. On the other hand, the ACE DD genotype was associated with a family history of ischemic heart disease in first degree relatives (X2 score = 9.04, P < 0.05). ACE and AGT gene polymorphisms may not play a role in the protective or accelerative effect against the development of diabetic nephropathy in the patients with or without proliferative retinopathy, but ACE gene polymorphism might be related to an arteriosclerotic family history in Japanese IDDM patients.

Topics: Adult; Albuminuria; Angiotensinogen; Blood Pressure; Cohort Studies; Creatine; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; DNA; Female; Glycated Hemoglobin; Humans; Hypertension; Japan; Male; Myocardial Ischemia; Ophthalmoscopy; Peptidyl-Dipeptidase A; Point Mutation; Polymorphism, Genetic; Renin-Angiotensin System

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.

Topics: Adult; Aged; Alleles; Amino Acid Substitution; Angiotensinogen; Body Mass Index; Case-Control Studies; Cholesterol; DNA Mutational Analysis; Female; Genes; Genetic Testing; Genotype; Humans; Hypertension; Male; Middle Aged; Mutation; Myocardial Infarction; Myocardial Ischemia; Phenotype; Pilot Projects; Retrospective Studies; Statistics as Topic; United Arab Emirates; Ventricular Dysfunction, Left