Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Quantitative in vitro autoradiography has identified high density ACE and AT(1) receptor binding at sites of cardiac injury in the adult rat, implicating Ang II, generated de novo at these sites (tissue Ang II) in contributing to repair. This hypothesis remains to be tested. In the study reported here we used a time-dependent rat model of cardiac injury wherein plasma levels of renin and Ang II are chronically suppressed by means of continuous treatment with aldosterone (0.75 microg/h) and 1% dietary NaCl. To further address a role for tissue Ang II in tissue repair, we administered oral valsartan (10 mg/kg/day) in combination with aldosterone/NaCl. On days 20 and 30 of each regimen, hearts were examined. In coronal sections, we assessed transcription factor NFkappaB activation (RelA subunit), inflammatory-cell infiltration and appearance of myofibroblasts by immunohistochemistry; mRNA expression of several inflammatory (NFkappaB-related) and fibrogenic (type I collagen) mediators of repair, using quantitative in situ hybridization; and ACE binding density, detected with quantitative in vitro autoradiography. Blood pressure was measured with a tail cuff. Untreated age- and sex-matched rats served as controls. On day 20, we found no evidence of cardiac injury, inflammation, or repair with aldosterone/NaCl treatment, with or without valsartan. In contrast, on day 30 of aldosterone/NaCl treatment, inflammatory cells and alpha-SMA-positive myofibroblasts colocalized with high-density ACE binding and histochemical evidence of fibrillar collagen accumulation at sites of microscopic scarring and perivascular fibrosis of intramyocardial coronary arteries that appeared in both right and left ventricles. The activation of NFkappaB and the increased mRNA expression of ICAM-1, MCP-1, TNF-alpha, TGF-beta(1), PAI-1, and type I collagen were also observed at these sites. Expression of vascular cell adhesion molecule-1 was unchanged. Valsartan significantly reduced (P <.01) the expression of these mediators and attenuated the expression of MCP-1. It reduced microscopic evidence of tissue damage and the extent of fibrosis. Blood pressure was increased in aldosterone-treated rats on days 20 and 30; this increase was suppressed by valsartan. We thus show that in this rat model of long-term aldosterone/NaCl administration, in which circulating Ang II is suppressed, AT(1) receptor-mediated actions of tissue Ang II are involved in regulating the expression of mediators of repair at vascular and nonvascular sites of cardiac injury, thereby implicating autocrine/paracrine properties of tissue Ang II in inflammatory and healing responses.
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PMID:Tissue angiotensin II in the regulation of inflammatory and fibrogenic components of repair in the rat heart. 1474 84

Genetic background appears to modulate the development of diabetic vascular complications. In particular, polymorphisms in the ACE gene have been associated with diabetic nephropathy and, in some studies, macrovascular complications. However, the links between ACE gene polymorphism and factors implicated in diabetes complications remain unknown. The aim of this study was to determine whether the ACE genotype could modify factors, such as transforming growth factor (TGF)-beta 1, involved in the complications of diabetes. For this purpose, congenic rats (L.BNAce10), differing from the LOU strain in only a small segment of chromosome 10 containing the ACE locus, were generated. These congenic rats have plasma ACE levels twice as high as the donor strain. Diabetes was induced in rats of both strains, and its effects on ACE and TGF-beta 1 expressions were evaluated in lungs and kidneys. In lung, the main source of ACE production, ACE mRNA levels and activity were higher in L.BNAce10 rats than in LOU rats. Diabetes increased ACE lung expression in rats of both strains in a similar manner. TGF-beta 1 expression was also higher in lungs of L.BNAce10 compared with LOU rats and was also increased by diabetes. Furthermore, a strong correlation was found between TGF-beta 1 and ACE expressions. In renal arterioles, ACE and TGF-beta mRNA expressions were higher in L.BNAce10 rats than LOU rats (both diabetic and nondiabetic). In these vessels, there was also a correlation between ACE and TGF-beta 1 expressions. Urine TGF-beta 1 concentration depended on the genotype and was further increased by diabetes. These results show that TGF-beta 1 expression is correlated with ACE expression and suggest that this growth factor could be a link between ACE gene polymorphism and diabetic vascular complications.
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PMID:Transforming growth factor-beta 1 production is correlated with genetically determined ACE expression in congenic rats: a possible link between ACE genotype and diabetic nephropathy. 1504 29

To compare diverse effects of angiotensin II type 1 receptor antagonists (irbesartan) and angiotensin converting enzyme inhibitors (imidapril) on left ventricular remodeling in spontaneously hypertensive rats (SHR). Thirty male SHR were randomly divided into three groups: SHR-IR (treated with irbesartan, 50 mg/kg), SHR-IM (imidapril, 3 mg/kg), SHR-C (placebo). Ten male Wistar Kyoto rats (WKY) treated with placebo acted as the control. All treatments were administered once daily from 14 to 27 weeks of age. Imidapril and irbesartan have the similar inhibitor effects on blood pressure and left ventricular mass indexes in SHR. Despite both drugs suppressed ERK-1 protein expression, decreased cardiomyocytes apoptosis index, blocked collagen type I deposition, reduced TGF-beta(1) gene expression in SHR, imidapril elicits a stronger inhibitory effect. Irbesartan had little effect on MKP-1 protein expression, but imidapril decreased it significantly. As a result, the ERK-1/MKP-1 ratio in SHR-IR was significantly greater than that in SHR-IM (P < 0.05). These results suggest that the balance between MKP-1 and ERKs in myocardial tissue is important for cardiac cell proliferation and growth. They also indicate that the similar efficacy of antihypertensive treatment in reducing blood pressure does not predict the similar capacity to control the individual facet of left ventricular remodeling. Irbesartan is more effective in regressing the homeostasis between ERK-1 and MKP-1, however imidapril is superior in suppressing apoptosis and collagen synthesis in cardiac tissue.
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PMID:Diverse effects of long-term treatment with imidapril and irbesartan on cell growth signal, apoptosis and collagen type I expression in the left ventricle of spontaneously hypertensive rats. 1514 28

The 31st Annual Meeting of the American Society of Nephrology, held in Philadelphia, Pennsylvania, USA, October 25-28, 1998, presented the newest advances in basic and clinical nephrology science. Several presentations discussed the results of studies with the newer immunosuppressants such as tacrolimus, sirolimus, mycophenolate mofetil and the anti-CD25 monoclonal antibodies, with the conclusion that studies on long-term use of these agents are needed. A number of other issues on immunosuppression protocols in renal transplantation were addressed during the meeting, including the subjects of steroid withdrawal and the role of TGF-beta in the development of chronic allograft nephropathy. The use of NESP in the treatment of renal anemia, the use of sildenafil to treat erectile dysfunction in hemodialysis patients, and the use of ACE inhibitors in nondiabetic renal patients were other important issues discussed at this meeting. Newer approaches to the treatment of hypertension discussed at the meeting highlighted the potential role of angiotensin II receptor antagonists in renal disease patients. Researchers also presented the promising results of a trial of a new, hybrid cell vaccine approach to the treatment of renal cell carcinoma.
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PMID:Recent advances in nephrology. 1561 34

Hepatitis C is reported to be associated with poorer renal survival in patients with diabetes. The mechanism for this observation has not been elucidated. Transforming growth factor beta-1 is involved in signaling for human disease involving fibrosis and excess matrix deposition including diabetic nephropathy. Hepatitis C virus core protein is known to upregulate transcription of TGF beta-1 in the liver and HCV patients have elevated levels of circulating TGF beta-1 versus controls. There is evidence that elevated circulating TGF beta-1 levels result in more rapid progression of nephropathy and that lowering circulating TGF beta-1 levels with an angiotensin converting enzyme inhibitor correlates with treatment efficacy in diabetic nephropathy. This paper outlines a hypothesis that the elevated level of circulating TGF beta-1 which is associated with HCV is a mediator of more rapid progression of diabetic renal disease in persons with HCV.
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PMID:Elevated circulating transforming growth factor beta-1 may explain poorer renal survival in type II diabetics with chronic hepatitis C. 1747 1

Monocrotaline (MCT), a pyrrolizidine alkaloid extracted from the shrub Crotalaria spectabilis, induces in the lungs of many mammalian species severe hypertension and fibrosis. Previous work with MCT-induced lung disease in rats has shown that some of the steps to progressive fibrosis can be interrupted or decreased by intervention with retinoic acid (RA) or with the angiotensin converting enzyme inhibitor, captopril. This report emphasizes the pathology and cytokines present in lungs of rats in the MCT model of hypertension and fibrosis in 8 treatment groups, six per group: (1) controls, not treated; (2) captopril; (3) RA; (4) combined captopril and RA. Groups 5-8 replicated groups 1-4 and also received MCT subcutaneously. Tissues were harvested at 28 days for histopathology and measurement of cytokines TGFbeta, TNFalpha, interleukin 6, and IFN_. TGFbeta was depressed at 28 days by MCT, an effect reversed by a combination of captopril and RA. RA influences production of an important Th1 cytokine, IFN_, and demonstrated the greatest limitation of MCT-induced TNFalpha. The MCT-induced lung pathology of vasculitis, interstitial pneumonia and fibrosis was limited by captopril. Smooth muscle actin was overexpressed in MCT treated animals receiving RA, an effect reduced with captopril. Overall, the study confirmed the existence of a protective effect for both captopril and RA from MCT-induced lung damage at 30 days. No synergistic or antagonistic activity was observed when the two drugs were administered together. Each of the drugs exerts different and particular effects on serum and tissue levels of various cytokines, suggesting that each drug is efficient at different points of attack in the control of lung fibrosis.
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PMID:Effects on cytokines and histology by treatment with the ACE inhibitor captopril and the antioxidant retinoic acid in the monocrotaline model of experimentally induced lung fibrosis. 1750 18

A role of ACE I/D polymorphism in the pathogenesis of abdominal aortic aneurysm (AAA) has been demonstrated, possibly due to the effect of angiotensin II on vascular tissue remodelling. Angiotensin II exerts profibrogenic effects through the local induction of TGF-beta. Dysregulated TGF-beta signalling may result from mutations in TGFBR1 and TGFBR2 genes, thus resulting in degenerative changes in the vessel wall. We performed a case-control study in order to investigate the role of TGFBR1 9A6A polymorphism as predisposing factor to AAA per se, and in the presence of ACE DD and AT1R 1166 CC genotypes in 201 AAA patients (mean age+/-S.D., 71.5+/-6.9) referred to the Unit of Vascular Surgery of the University of Florence, compared with 252 healthy controls (mean age+/-S.D., 70.6+/-8.6). A significant difference in genotype distribution and allele frequency between patients and controls was found for ACE, but not for AT1R and TGFBR1 polymorphisms. At univariate analysis a significant association between ACE DD, but not AT1R CC and TGFBR1 6A allele, and the susceptibility to the disease was found [ACE DD OR=1.86 (95% CI 1.26-2.76), p=0.002]. After adjustment for age, gender, traditional cardiovascular risk factors, and CAD, PAD and CVD, ACE DD genotype still affected the susceptibility to AAA [OR=2.13 (95% CI 1.06-4.28), p=0.03], and the contemporary presence of ACE DD genotype and TGFBR1 6A allele, increased the predisposition to the disease [OR=5.09 (95% CI 1.44-18.02), p=0.01]. This study, which demonstrates an interaction between ACE and TGFBR1 genes in predisposing to AAA, may provide further information on the mechanisms contributing to AAA susceptibility, and offer a topic for future larger studies.
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PMID:ACE and TGFBR1 genes interact in influencing the susceptibility to abdominal aortic aneurysm. 1855 62

After myocardial infarction (MI), the heart may undergo progressive ventricular remodeling, resulting in a deterioration of cardiac function. TGF-beta is a key cytokine that both initiates and terminates tissue repair, and its sustained production underlies the development of tissue fibrosis, particularly after MI. We investigated the effects of a novel orally active specific inhibitor of the TGF-beta receptor 1 (SD-208) in an experimental model of MI. Mice underwent ligation of the left coronary artery to induce MI and were subsequently treated for 30 d after infarction with either SD-208 or a vehicle control. Blockade of TGF-beta signaling reduced mean arterial pressure in all groups. SD-208 treatment after MI resulted in a trend for reduced ventricular and renal gene expression of TGF-beta-activated kinase-1 (a downstream modulator of TGF-beta signaling) and a significant decrease in collagen 1, in association with a marked decrease in cardiac mass. Post-MI SD-208 treatment significantly reduced circulating levels of plasma renin activity as well as down-regulating the components of the cardiac and renal renin-angiotensin system (angiotensinogen, angiotensin converting enzyme, and angiotensin II type I receptor). Our findings indicate that blockade of the TGF-beta signaling pathway results in significant amelioration of deleterious cardiac remodeling after infarction.
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PMID:Transforming growth factor-beta blockade down-regulates the renin-angiotensin system and modifies cardiac remodeling after myocardial infarction. 1865 7

1. Epidemiological aspects: There is evidence that the pandemic of DM is entering a stabilization phase, with a slight downturn in the rates of ESRD attributed to DM in the United States. 2. New pathogenic and progression mechanisms of renal disease are proposed: 1) Intraglomerular hyperpressure with phenotypical cell changes, inducing TGF-beta activation; 2) Genetic polymorphisms, with candidate genes in chromosomes 18q, 3q, 7p and others; 3) Endothelial dysfunction as an injury initiating mechanism, demonstrated in the eNOS knockout rat; 4) Isoforms of PKC molecules that favor progression of nephropathy. 3. Importance of metabolic syndrome as a progression factor of chronic renal disease. 4. Increased CV risk in patients treated with thiazolidinediones (glitazones) -Hydrosaline retention and heart failure. 5. Recent studies: ADVANCE study: Combined treatment with an ACE inhibitor (perindropil) and a diuretic (indapamide) in fixed doses helps to reduce CV risk and overall mortality.DREAM study: Ramipril does not reduce the occurrence of DM2, but does improve reversion to normoglycemia. AVOID study: Direct renin inhibitors add greater antihypertensive and antiproteinuric efficacy. 6. New therapeutic targets: Antifibrotic, anti-inflammatory and antiproteinuric effects of sulodexide, isosorbide mononitrate, PKC inhibitors and others. 7. The most effective strategy continues to be intensive, multifactorial and multidisciplinary management of the type 2 diabetic patient, as shown by long-term follow-up in the Steno-2 study.
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PMID:[Advances in diabetes mellitus, diabetic nephropathy, metabolic syndrome and cardio-vascular-renal risk]. 1884 25

Systemic sclerosis (SSc) is a chronic autoimmune disease with clinical manifestations resulting from immune activation, fibrosis development, and damage of small blood vessels. Our aim was to critically illustrate the available data on the new treatments proposed for SSc to provide a clinically oriented overview of the current evidence. PubMed was used for literature search using "scleroderma" and "therapy" to identify all articles published on indexed journals between 1972 and 2008. The search was limited to publications in English and produced a total of 3,441 references, which included 735 review articles. These citations were then screened for articles dealing with the most recent therapy options for SSc, and 214 articles were selected for evaluation and discussion. Methotrexate, cyclophosphamide, calcium channel blockers, angiotensin converting enzyme inhibitors, prostacyclin analogues, D-penicillamine, and extracorporeal photopheresis are the most widely studied treatments for SSc and were considered as practiced treatments. Other therapeutic approaches have been developed more recently and include endothelin receptor antagonists and phosphodiesterase-5 inhibitors for pulmonary arterial hypertension and peripheral vascular disease. High-dose immunosuppression and stem cell transplantation constitute a promising treatment and data from randomized controlled trials are awaited. Intravenous gamma globulins, mycophenolate mophetil, collagen tolerance induction, rituximab, fluoxetine, pirfenidone, relaxin, halofuginone, anti-TGF-beta antibodies, and tyrosine kinase inhibitors awaits more solid data. The clinical management of patients with SSc remains a challenge and currently involves practiced and newly proposed therapeutic approaches. The disease pleiomorphism poses numerous difficulties to determine ideal outcomes to be used in clinical trials.
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PMID:Recent advances in the treatment of systemic sclerosis. 1913 59


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