Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously identified the gene expression of renin-angiotensin system in human monocyte-derived dendritic cells (DCs). This study was conducted to examine the mechanisms by which angiotensin II and captopril, the inhibitor of the angiotensin-converting enzyme (ACE), affect human DCs. In DCs, lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-alpha), interleukin-(IL)-1alpha, IL-10, IL-12, and IL-18 was significantly inhibited by captopril. In contrast, angiotensin II treatment resulted in a significant increase in TNF-alpha and IL-6 protein biosynthesis by DCs. In addition, we have studied the global expression of 2400 genes in DCs from two donors. Here, we demonstrated the specific down-regulation of the ACE gene expression in captopril-treated DCs. Our finding indicates the possible activation of NF-kappaB through the up-regulation of expressions of MEFV gene (encoding PYRIN protein) and heterogeneous nuclear ribonucleoprotein R in DCs. This is the first study on the modulation of cytokine and gene expression by angiotensin II and captopril in DCs.
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PMID:Activation and suppression of renin-angiotensin system in human dendritic cells. 1214 50

Excessive biohumoral activation participates in the pathophysiology and progression of congestive heart failure (CHF). Pharmacological inhibition of the renin-angiotensin-aldosterone and beta-adrenergic systems improves the mortality and morbidity of this disease. Among other detrimental molecules, two local factors, tumor necrosis factor (TNF)-alpha and endothelin (ET) both contribute to the worsening of CHF. TNF-alpha can induce many of the cellular modifications typically associated with CHF, such as myocyte death, interstitial tissue derangement and negative inotropism. On the other hand ET promotes vasoconstriction, and cell growth and proliferation. On the premise of some favorable experimental studies, selective antagonism of TNF-alpha or ET has been tested in clinical trials in order to control the progression of or even reverse CHF. However, contrasting results have been obtained so far with either approach, in accordance with other unfavorable data from animal models of heart failure. Etanercept (Enbrel, a recombinant dimer of two p75sTNFR molecules fused to the Fc fragment of human IgG1) has proved to be useful and effective in basic and animal experiments, while contrasting data have been reported on humans. The Randomized EtaNErcept Worldwide evALuation (RENEWAL) trial has recently been prematurely stopped due to impossibility of showing statistically significant results with the pre-specified sample size. Results of phase II to III clinical trials on different ET receptor antagonists in CHF have yielded conflicting results, so that none of the agents of this class have been labeled for CHF. The mechanisms by which TNF-alpha and ET might exert their negative biological actions are discussed together with an analysis of the possible reasons why they have failed so far in human CHF.
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PMID:[Refractory heart failure. Antagonism of tumor necrosis factor alpha and endothelin in humans: 2 promises still to be honored]. 1240 34

Angiotensin (Ang) II promotes renal infiltration by immunocompetent cells in double-transgenic rats (dTGRs) harboring both human renin and angiotensinogen genes. To elucidate disease mechanisms, we investigated whether or not dexamethasone (DEXA) immunosuppression ameliorates renal damage. Untreated dTGRs developed hypertension, renal damage, and 50% mortality at 7 weeks. DEXA reduced albuminuria, renal fibrosis, vascular reactive oxygen stress, and prevented mortality, independent of blood pressure. In dTGR kidneys, p22phox immunostaining co-localized with macrophages and partially with T cells. dTGR dendritic cells expressed major histocompatibility complex II and CD86, indicating maturation. DEXA suppressed major histocompatibility complex II+, CD86+, dendritic, and T-cell infiltration. In additional experiments, we treated dTGRs with mycophenolate mofetil to inhibit T- and B-cell proliferation. Reno-protective actions of mycophenolate mofetil and its effect on dendritic and T cells were similar to those obtained with DEXA. We next investigated whether or not Ang II directly promotes dendritic cell maturation in vitro. Ang II did not alter CD80, CD83, and MHC II expression, but increased CCR7 expression and cell migration. To explore the role of tumor necrosis factor (TNF)-alpha on dendritic cell maturation in vivo, we treated dTGRs with the soluble TNF-alpha receptor etanercept. This treatment had no effect on blood pressure, but decreased albuminuria, nuclear factor-kappaB activation, and infiltration of all immunocompetent cells. These data suggest that immunosuppression prevents dendritic cell maturation and T-cell infiltration in a nonimmune model of Ang II-induced renal damage. Ang II induces dendritic migration directly, whereas in vivo TNF-alpha is involved in dendritic cell infiltration and maturation. Thus, Ang II may initiate events leading to innate and acquired immune response.
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PMID:Immunosuppressive treatment protects against angiotensin II-induced renal damage. 1241 15

Insulin resistance and/or compensatory hyperinsulinemia are associated with hypertension, obesity, dyslipidemia, and glucose intolerance. Insulin resistance and hyperinsulinemia are considered to increase blood pressure through sympathetic nervous system activation, renin-angiotensin system stimulation, and vascular smooth muscle cell proliferation. Leptin, magnesium ions, nitric oxide, endothelin, peroxisome proliferator-activated receptor gamma, and tumor necrosis factor-alpha also modulate blood pressure. Decreasing insulin resistance by lifestyle modification including diet, weight loss, and physical exercise has been shown to reduce blood pressure. Angiotensin-converting enzyme inhibitors have a beneficial effect on insulin resistance. On the other hand, the angiotensin II antagonist, losartan, does not affect insulin sensitivity. The selective alpha1-blockers have a favorable metabolic profile producing increases in insulin sensitivity. A short-acting type calcium channel blocker seems to decrease insulin sensitivity. On the other hand, long-acting type calcium channel blockers improve insulin sensitivity. Thiazide diuretics and most of the beta-blockers decrease insulin sensitivity. Vasodilatory beta-blockers have been reported to improve insulin sensitivity. Use of low-dose diuretics avoids the adverse effects seen with conventional doses.
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PMID:Hypertension and insulin disorders. 1241 78

Patients with congestive heart failure (CHF) have a high incidence of ventricular arrhythmias and sudden arrhythmic death. CHF entails profound and complex abnormalities in humoral responses that are thought to promote arrhythmic events. However, it is unknown which of the many endogenous mediators that accumulate as part of neurohormonal activation is important in arrhythmogenesis in the setting of CHF. The study included 83 patients admitted to the hospital for treatment of decompensated CHF. Neurohormonal and cytokine activation was assessed by measuring plasma renin activity, aldosterone, norepinephrine, endothelin-1, tumor necrosis factor-alpha, and interleukin-6 levels. Atrial and ventricular arrhythmic events were assessed by 24-hour Holter monitoring. In a univariate analysis, a highly significant, positive relationship was found between plasma endothelin-1 levels and the average hourly total premature ventricular beats (P = 0.003), the frequency of ventricular pairs (P = 0.0003), and the frequency of ventricular tachycardia episodes (P = 0.001). After inclusion of clinical variables, drug therapies, neurohormones, and cytokine levels in a multivariate analysis, the positive relationship between plasma endothelin-1 level and the average hourly total premature ventricular beats (P = 0.008), the frequency of ventricular pairs (P = 0.007), and ventricular tachycardia episodes (P = 0.009) remained independent. No association between other neurohormones or cytokines and arrhythmic events was demonstrated. The results of the present study suggest that increased endothelin-1 concentrations may be involved in promoting the occurrence of ventricular ectopy in patients with decompensated CHF. Proarrhythmic effects may account, in part, for the poor outcome associated with increased endothelin-1 levels in patients with decompensated CHF.
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PMID:Neurohumoral activation and ventricular arrhythmias in patients with decompensated congestive heart failure: role of endothelin. 1269 70

It has been reported that proinflammatory cytokine activation is associated with both mesenteric venous congestion and peripheral tissue underperfusion in advanced chronic heart failure. The aim of our study was to investigate if plasma amylase (as an easily approached marker of a low-grade peripheral organ injury caused by elevated systemic venous pressure and reduced cardiac output) is elevated in severe heart failure and if this elevation is correlated with cytokine and neurohormonal activation in the plasma of heart failure patients. Plasma levels of amylase, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), norepinephrine, and renin activity were measured in 43 severe heart failure patients (ischemic, 28; dilated, 15; left ventricular ejection fraction [LVEF] 27 +/- 3%; New York Heart Association [NYHA] classes III-IV), in 37 mild heart failure patients (ischemic, 26; dilated, 11; LVEF, 33 +/- 5%; NYHA classes I-II), and in 20 age-matched and gender-matched healthy controls. NYHA III-IV heart failure patients exhibited significantly higher plasma levels of amylase (342 +/- 19 vs. 174 +/- 13 U/L, p < 0.01), TNF-alpha (6.2 +/- 0.5 vs. 4.2 +/- 0.3 pg/ml, p < 0.01), IL-6 (5.9 +/- 0.3 vs. 4.4 +/- 0.3 pg/ml, p < 0.05), GM-CSF (21.2 +/- 2.7 vs. 4.1 +/- 0.9 pg/ml, p < 0.001), and neurohormones (both p < 0.001) compared with NYHA I-II heart failure patients and healthy controls (amylase, 165 +/- 11 U/L, p < 0.01; TNF-alpha, 2.7 +/- 0.3 pg/ml, p < 0.001; IL-6, 3.2 +/- 0.2 pg/ml, p < 0.01; GM-CSF, 3.1 +/- 0.7 pg/ml, p < 0.001). Only in NYHA III-IV heart failure patients, plasma amylase levels were significantly correlated with plasma IL-6 activity (r = 0.86, p < 0.001), plasma norepinephrine levels (r = 0.82, p < 0.001) and right atrial pressure (r = 0.52, p < 0.05). Additionally, circulating IL-6 was also significantly correlated with plasma norepinephrine (r = 0.86, p < 0.001) and right atrial pressure (r = 0.57, p < 0.01). In conclusion, plasma amylase levels were elevated in severe heart failure patients and correlated well with circulating IL-6 activation, possibly as a result of both mesenteric venous congestion and impaired peripheral tissue perfusion observed in advanced chronic heart failure. However, the lack of association between plasma IL-6 and amylase levels in mild heart failure patients indicates an independent correlation of each variable with the functional status of the disease.
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PMID:Elevated plasma amylase levels in advanced chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy: correlation with circulating interleukin-6 activity. 1285 59

Chronic heart failure (CHF) is characterized by the activation of neurohormones and cytokines. This study determined whether peak oxygen uptake (VO2) can be predicted by the degree of neurohormonal and cytokine activations in CHF. Plasma norepinephrine. epinephrine, renin-angiotensin system activity, ANP, BNP, and serum interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha were measured in 84 CHF patients (age, 59 +/- 1 years, LVEF, 36 +/- 1%) and 34 controls. Maximal cardiopulmonary exercise testing was performed. Peak VO2 (Controls vs CHF: 27.8 +/- 1.3 vs 18.2 +/- 0.5 mL/min/kg, P < 0.0001) was lower in CHF. Patients with CHF had increased plasma norepinephrine (211 +/- 11 vs 315 +/- 24 pg/mL), renin activity (1.2 +/- 0.2 vs 6.2 +/- 1.1 ng/mL/hr), ANP (22 +/- 3 vs 72 +/- 7 pg/mL), and BNP levels (18 +/- 3 vs 200 +/- 25 pg/mL) (all P < 0.01). Serum IL-6 (1.1 0.1 vs 2.4 +/- 0.3 pg/mL) and TNF-alpha (2.7 +/- 0.2 vs 4.0 +/- 0.3 pg/mL) levels were higher in CHF (both P < 0.001). Univariate analysis revealed that age (P < 0.001), cardiothoracic ratio (P < 0.001), norepinephrine (P < 0.0001), ANP (P < 0.001), BNP (P < 0.01), and log IL-6 (P < 0.05) were significantly related with peak VO2. Stepwise regression analysis indicated that plasma norepinephrine and ANP emerged as significant determinants of peak VO2, independent of patient age (overall R = 0.61, P < 0.0001). In summary, patients with CHF exhibited activation of neurohormones and proinflammatory cytokines. Among the elevated hormonal and cytokine markers, plasma norepinephrine and ANP levels were independent predictors of exercise capacity.
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PMID:Neurohormonal determinants of peak oxygen uptake in patients with chronic heart failure. 1458 54

Immunoglobulin A (IgA) nephropathy is an immune-complex-mediated glomerulonephritis characterized by the presence of immunoglobulin A deposits in mesangial and paramesangial regions. The patients with IgA nephropathy present with varying clinical symptoms (eg, microhematuria with preserved renal function or progressive deterioration of renal functions resulting in end-stage renal disease). The factors involved in the pathogenetic mechanisms of IgA nephropathy include (1). environmental factors, (2). genetic factors, (3). abnormality of the IgA1 molecule, and (4). various inflammatory mediators. The gene polymorphism studies for human leukocyte antigen (HLA), renin-angiotensin-aldosterone system, and selectin gene clusters, suggest a certain degree of genetic predisposition in patients for IgA nephropathy. Also, the genome-wide screening in familial IgA nephropathy showed linkage of IgA nephropathy to the 6q22-23 chromosome. Besides genetic influence in its pathogenesis, aberrant galactosylation in serum IgA and IgA1 eluted from kidneys with IgA nephropathy has been observed, and conceivably such abnormalities induce the expression of various cytokines, interleukin (IL)-6, platelet-derived growth factor (PDGF), tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta1 in the renal cells, which contributes to further glomerular injury. Despite an enormous amount of information available in the literature, further studies are needed to delineate the precise pathogenetic mechanisms involved in primary IgA nephropathy and also to facilitate the development of newer therapeutic interventions.
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PMID:Pathogenesis of IgA nephropathy. 1463 63

It has been shown that the renin-angiotensin system (RAS) plays key roles in the development of fibrosis in numerous organs, including the liver. Other studies have suggested that the RAS also may play roles in diseases of chronic inflammation. However, whether the RAS also can mediate acute inflammation in liver is unclear. The purpose of this study therefore was to determine the effect of the RAS inhibitors captopril and losartan on acute liver damage and inflammation caused by hepatic ischemia and subsequent reperfusion. Accordingly, male rats were subjected to 1 hour of hepatic ischemia (70%) followed by reperfusion; animals were killed 3, 8, or 24 hours after reperfusion. The effect of captopril or losartan (100 or 5 mg/kg intragastrically, respectively) was compared with that of vehicle (saline). The expression of angiotensinogen in liver increased fivefold 3 hours after reperfusion. Indices of liver damage and inflammation (e.g., alanine aminotransferase levels, pathological features, tumor necrosis factor-alpha levels, and intercellular adhesion molecule-1 expression) all were significantly elevated in vehicle-treated animals after hepatic ischemia and subsequent reperfusion. Ischemia and reperfusion also caused an increase in the accumulation of protein adducts of 4-hydroxynonenal, an index of oxidative stress. Captopril or losartan treatment showed profound protective effects under these conditions, significantly blunting the increase in all these parameters caused by ischemia and reperfusion. In conclusion, RAS inhibitors prevent acute liver injury in a model of inflammation caused by ischemia and reperfusion. These data further suggest that the RAS may play a key role in mediating such responses in the liver and suggest a novel role for this system.
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PMID:Role of the renin-angiotensin system in hepatic ischemia reperfusion injury in rats. 1534 96

The purpose of the study was to examine the effect of fosinopril on the magnitude of neurohumoral and proinflammatory activation in patients with severe heart failure (HF). Twenty-eight patients aged 52-68 years who had Functional Class (FC) III-IV HF that had developed due to coronary heart disease were examined. All the patients were divided into 2 groups (with 14 patients in each group) and they received routine therapy including an angiotensin-converting enzyme inhibitor (ACEI) and a beta-adrenoblocker. Group 1 patients were given the ACEI fosinopril in a dose of 10-20 mg/day, Group 2 patients took captopril in a dose of 50-75 mg/day. The course of therapy was 12 weeks. All the patients underwent echocardiography by the routine procedure. The plasma levels of angiotensin-II, aldosterone, and brain natriuretic peptide (BNUP) were determined by radioimmunoassay. The plasma contents of tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein (C-RP) were verified by enzyme immunoassay. An analysis of the findings indicated that during therapy the FC of HF decreased on the average by 10.9% in Group 1 and by 11. 7% in Group 2 (p = 0.14). With this, fosinopril was superior to captopril not only in its capacity of improving overall left ventricular contractile function, but it was characterized by a more pronounced effect on regression of the plasma pool of C-RP and TNF-alpha. The marked depressive action of the ACEI fosinopril on the plasma pool of products of the renin-angiotensin system, BNUP, and proinflammatory cytokines may be considered to be as a basis for preferably prescribing the agent to patients with severe HF.
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PMID:[Effect of fosinopril on the rate of neurohumoral and proinflammatory activation in patients with heart failure]. 1554 Apr 18


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