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

---

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

Angiotensin II (AT II) is a final product of the renin-anglotensin-aldosterone system (RAS) and presents one of the most influential factors in the pathogenesis of atherosclerosis, acute coronary syndrome, myocardial dysfunction and heart failure. ACE-inhibitors (ACEI), beside beta adrenergic blockers, are a cornerstone of the current chronic heart failure (CHF) treatment. Evidence based medicine has not yet proved any significant beneficial effects of ACEI in patients with unstable angina pectoris (UAP), although according to the SoLVD study testing the possible effects of ACEI in patients with significant left ventricular dysfunction and/or CHF, there was a significant hospitalization rate reduction as well as less transformation of UAP to myocardial infarction in patients treated with ACEI. In the GISSI 3, ISIS 4 and CCS studies, ACEI was given within the first 24 hours and continued for 4-6 weeks. According to pooled results, ACE inhibitor could save 11/1000 patients with ST-elevation myocardial infarction (STEMI) and only 1/1000 patients with non ST-elevation myocardial infarction (NSTEMI). In the SAVE, AIRE and TRACE studies, ACEI was started later, i.e. 3-16 days after acute myocardial infarction and continued for several years. ACEI therapy resulted in a significantly lower mortality during the first year, and an even 20% relative reduction in the total mortality during the 4-year follow up. The effects of ACEI were even more prominent in more severe myocardial dysfunction, as it was well known that they could slow or stop unfavorable myocardial remodeling. Conclusively, ACEI should be given as early as possible to all patients with acute myocardial infarction, if no contraindications. The HOPE study showed efficacy of ACEI in the primary prevention of ischemic heart disease in high risk individuals, and the EUROPA study showed a favorable effect of ACEI in the secondary prevention of ischemic heart disease in low risk patients. According to these findings, ACEI should be given permenantly following myocardial infarction. These findings suggest the need of a permanent treatment with ACEI in patients having sustaned myocardial infarction. Angiotensin-1 receptor antagonists (AT-1 antagonists) are a newer generation of neurohormonal antagonists, which block the effects of AT II produced not only through a classic, ACE-dependent pathway but also via alternative pathways (non ACE-dependent) and selectively bind to AT-1 receptors for AT II. Therefore, they have some theoretical advances in comparison with ACEI. There are 2 relevant studies elucidating their possible role in treating patients with or post-myocardial infarction. The OPTIMAAL study did not prove losartan to be better than an ACEI (captopril), while the VALIANT study showed that the effects of valsartan vs. captopril were statistically nonsignificantly different. Furthermore, there is no sense to combine AT-1 antagonist and ACEI, while a combination of AT-1 antagonist and a beta blocker is justified. In other words, AT-1 antagonist (the class effect is disputable) should be given to patients with acute myocardial infarction or to post-myocardial infarction patients who cannot take ACEI.
...
PMID:[ACE inhibitors and angiotensin II receptor antagonists in acute coronary syndrome]. 1520 98

Angiotensin II (Ang II) is an octapeptide with a central role in cardiovascular homeostasis and actions in several organs including the adrenal gland, kidney, brain, heart, smooth muscle cells and sympathetic nervous system. At these levels it is involved in cellular proliferation and apoptosis, cellular migration, inflammation, synthesis and release of various mediators such as platelet-derived growth factor and endothelin-1) and in the synthesis of extracellular matrix. Traditionally, Ang II was considered a systemic hormone regulating blood pressure, aldosterone release and sodium reabsorption. However, nowadays it is known that this mediator is also formed at the tissue level in the brain, kidney and heart, suggesting local paracrine and autocrine action. At the vascular level, with the exception of renin, all other components of this system are locally produced in vascular adventitia, smooth muscle cells or endothelial cells. In the heart all the components have also been found and their response to humoral, nervous and mechanical stimuli suggests a working local system. Ang II exerts its biological action through two main receptor subtypes: AT-1 and AT-2. The AT-1 receptor is responsible for many of the physiological effects of Ang II in cardiac, vascular, kidney, brain and endocrine cells. Expression of the AT-2 receptor is higher in fetal tissue, especially in mesenchymal tissue (like the tongue, endoderm and diaphragm), decreasing after birth. Its effects are frequently opposite to those mediated bt the AT-1 receptor. Its role in cardiovascular pathophysiology is not yet established. Ang II recruits a complex cascade of intracellular second messengers with different patterns of temporal activation: immediate (in seconds), early (in minutes) and late (in hours). Clinical trials using angiotensin converting enzyme inhibitors (ACEi) and AT-1 receptor antagonists (ARA) have shown improvement in morbidity and mortality in hypertension, congestive heart failure and after myocardial infarction. Although many of the mechanisms underlying these actions are not fully understood, there are no doubts about the beneficial effects of inhibiting this system in the treatment of several cardiovascular diseases.
...
PMID:[Renin-angiotensin system and its role in cardiovascular physiopathology and therapy]. 1522 51

Two endothelium-derived factors, endothelin (ET), a vasoconstrictor, and vascular endothelial growth factor (VEGF), an angiogenic factor are thought to be involved in the pathogenesis of diabetic vascular complications. The aim of this study was to determine the effects of an angiotensin II type I (AT-1) receptor antagonist and an ACE inhibitor on the pathogenesis of VEGF and ET-1-mediated kidney disease in STZ-induced diabetic rats. Two days after STZ administration, diabetic rats were treated for 8 weeks with enalapril maleate, an ACE inhibitor, candesartan cilexetil, an AT-1 receptor antagonist, or saline. Urinary albumin and N-acetyl beta-D glucosaminidase (NAG) excretion as well as the VEGF protein content in the kidney were all found to be elevated in diabetic rats. Administration of enalapril maleate or candesartan cilexetil decreased the level of microalbuminuria and NAG excretion in diabetic rats. Administration of enalapril maleate also suppressed the elevated renal VEGF protein content in these animals while candesartan cilexetil treatment had no effect. Serum ET-1 and VEGF levels were unchanged by these treatments. These data support a role for AT-1 receptor antagonists and ACE inhibitors in the prevention of diabetic nephropathy, and suggest that the former may work by reducing renal VEGF levels.
...
PMID:Possible role of VEGF in the progression of kidney disease in streptozotocin (STZ)-induced diabetic rats: effects of an ACE inhibitor and an angiotensin II receptor antagonist. 1530 28

In diabetes oxidative stress plays a key role in the pathogenesis of vascular complications, and an early step of such damage is considered the development of an endothelial dysfunction. Hyperglycemia directly promotes an endothelial dysfunction inducing process of overproduction of superoxide and consequently peroxynitrite that damages DNA and activates the nuclear enzyme poly(ADP-ribose) polymerase. This process, depleting NAD+, slowing glycolysis, ATP formation and electron transport, results in acute endothelial dysfunction in diabetic blood vessels and contributes to the development of diabetic complications. Classic antioxidants, like vitamin E, failed to show beneficial effects on diabetic complications probably due to their only "symptomatic" action. It is now evident that, statins, ACE inhibitors, AT-1 blockers, calcium channel blockers and thiazolinediones have a strong intracellular antioxidant activity, and it has been suggested that many of their beneficial ancillary effects are due to this property. Statins increase NO bioavailability and decrease superoxide production, probably interfering with NAD(P)H activity and modulating eNOS expression. ACE inhibitors and AT-1 blockers prevent hyperglycemia-derived oxidative stress modulating angiotensin action and production. This effect is of particular interest because hyperglycemia is able to directly modulate cellular angiotensin generation. Calcium channel blockers inhibit the peroxidation of cell membrane lipids and their subsequent intracellular translocation. Thiazolinediones bind and activate the nuclear peroxisome proliferator-activated receptor gamma, a nuclear receptor of ligand-dependent transcription factors. The inhibition of this receptors lead to inhibition of the inducible nitric oxide synthase and consequently reduction of peroxynitrite generation. This preventive activity against oxidative stress generation can justify a large utilization and association of this compound for preventing complications in diabetic patients, where antioxidant defences have been shown to be defective.
...
PMID:Antioxidant therapy in diabetic complications: what is new? 1532 Aug 13

Heart failure is highly prevalent in the population with chronic kidney disease. Upon starting dialysis, 37% of patients will have had a previous episode of heart failure, doubling the risk of death. Both systolic and/or diastolic function may be impaired. 15% of patients starting dialysis therapy have systolic dysfunction of the left ventricle. The prevalence of diastolic dysfunction at dialysis inception is unknown, but is likely to be high. Either systolic or diastolic dysfunction can lead to clinically evident congestive heart failure. Hypertension and coronary heart disease are important causes of myocardial dysfunction in end-stage renal disease. Individuals with chronic kidney disease are at a very high risk for the development and progression of cardiovascular disease. The increased risk of cardiovascular disease is due to a higher prevalence of both traditional risk factors as well as nontraditional "uremia-related" risk factors. The prevalence of coronary artery disease (CAD) approaches 40% among patients starting dialysis. About 70-80% of these patients have hypertension. Anaemia is a known risk factor for left ventricular hypertrophy (LVH) and dilatation, heart failure and death. The diagnosis and treatment of heart failure in the patients with chronic kidney disease (CKD) are similar to that recommended for patients without CKD. The potent drugs like ACE-I, AT-1 antagonists, beta-receptor antagonists are the main tools in nowadays treatment of CHF. New therapeutic regiments using natriuretic peptides are being evaluated in clinical settings.
...
PMID:Heart failure in patients with chronic kidney disease. 1563 34

The sarcoplasmic reticulum (SR) is a major player in maintaining cardiac function, as it is intimately involved in the regulation of Ca2+-movements on a beat-to-beat basis. SR dysfunction due to abnormalities in SR protein content has been reported in different cardiac diseases such as ischaemic heart disease, myocardial infarction, congestive heart failure and various cardiomyopathies; thus the genes expressing the SR Ca2+-pump, Ca2+-channels, calsequestrin, phospholamban and other regulatory proteins are considered important targets for drug development. In our experience, ischaemic preconditioning (IP) and pharmacological therapies, such as anti-oxidants, beta-adrenergic receptor blockers, angiotensin receptor (AT-1) blockers, angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers are effective therapies that improve cardiac performance in the failing heart by improving SR function. Accordingly, this paper is intended to shed light on the knowledge in the field of cardiac therapy targeted to improve and protect SR function.
...
PMID:Sarcoplasmic reticulum and cardiac oxidative stress: an emerging target for heart disease. 1599 77

In diabetes, oxidative stress plays a key role in the pathogenesis of vascular complications, and an early step of such damage is considered to be the development of an endothelial dysfunction. Hyperglycemia directly promotes an endothelial dysfunction inducing process of overproduction of superoxide and consequently peroxynitrite, that damages DNA and activates the nuclear enzyme poly(ADP-ribose) polymerase. This process, depleting NAD+, slowing glycolsis, ATP formation and electron transport, results in acute endothelial dysfunction in diabetic blood vessels and contributes to the development of diabetic complications. These new findings may explain why classical antioxidants, like vitamin E, that work scavenging already formed toxic oxidation products, have failed to show beneficial effects on diabetic complications, and suggest new and attractive "causal" antioxidant therapy. New, low molecular mass compounds that act as SOD or catalase mimetics or L-propionyl-carnitine and lipoic acid, that work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such strategy, and preliminary studies support this hypothesis. This "causal" therapy would also be associated with other promising tools such as LY 333531, PJ34 and FP15, which block protein kinase beta isoform, poly(ADP-ribose) polymerase and peroxynitrite, respectively. It is now evident that, statins, ACE inhibitors, AT-1 blockers, calcium channel blockers and thiazolidinediones have a strong intracellular antioxidant activity, and it has been suggested that many of their beneficial ancillary effects are due to this property. This preventive activity against oxidative stress generation can justify a large utilization and association of this compounds for preventing complications in diabetic patients where antioxidant defences have been shown to be defective.
...
PMID:Molecular targets of diabetic vascular complications and potential new drugs. 1602 69

Heart failure (HF) is a multifactorial and progressive disease that has been associated with multiple systemic and vascular alterations. Previous reports from our laboratory showed that in 2-month-old Bio-To2 Syrian cardiomyopathic hamsters (SCH) that have not yet developed the clinical manifestations of HF, the vascular contractility induced by 0.1 microM angiotensin II was approximately 35% greater than in control animals. This finding was observed concomitantly with an increased aortic ACE activity. To further evaluate the mechanisms underlying angiotensin II-enhanced vascular contraction, concentration-response curves for angiotensin II (0.01 nM-10 microM) were constructed before and after the addition of prazosin (alpha-1 blocker), NS-398 (selective COX-2 blocker) and BQ-123 (ET-1A-receptor antagonist) in aortic rings from 2-month-old SCH. The binding capacity and affinity of the AT-1 receptors were also evaluated in aortic homogenates using 125I-angiotensin II. Age-matched golden hamsters were used as controls (CT). Our results indicate that incubation with either 10 microM prazosin or 10 microM NS-398 did not modify EC50 or Emax values for angiotensin II indicating that norepinephrine and prostaglandins are not involved in the enhanced contractile action of angiotensin II. However, 10 microM BQ-123 reduced by 40% the contraction induced by 1.0 microM angiotensin II (from 1.05+/-0.04 to 0.6475+/-0.06 g/mg tissue, n = 5, P < 0.05), suggesting that in cardiomyopathic hamsters, the action of angiotensin II is mediated in part by ET-1. At lower angiotensin II concentration (0.1 microM), the ET-1-dependent contraction decreases to 29%. In addition, although dissociation constants for labeled angiotensin II were found to be similar in the aorta of SCH and control animals (K(D): CT = 7.8 nM and SCH = 5.1 nM), 125I-angiotensin II binding capacity was about 2-fold greater in SCH than in controls (Bmax: SCH = 1113 and CT = 605 fmol/mg protein). Altogether these results suggest that in 2-month-old SCH the enhanced response of angiotensin II in the vasculature is mediated both by an increased binding capacity for the hormone and facilitation of the ET-1 action.
...
PMID:Increased vascular angiotensin II binding capacity and ET-1 release in young cardiomyopathic hamsters. 1650 5

The expression of the Receptor for Advanced Glycation Endproducts (RAGE) is upregulated at sites of vascular inflammation and plays a crucial role in vessel homeostasis. Soluble RAGE (sRAGE), a truncated soluble form of the receptor, acts as a decoy and prevents the inflammatory response mediated by RAGE activation. sRAGE has recently emerged as a biomarker in several RAGE-mediated vascular disorders, including coronary artery disease, hypertension, diabetic vasculopathy and Kawasaki disease. Given the pivotal role played by RAGE and sRAGE in numerous vascular disorders, there is a growing need to understand how drugs can modulate the RAGE axis in different disease conditions. In this regard, there is evidence to suggest that traditional cardiovascular drugs (statins, thiazolidinediones, ACE-inhibitors, AT-1 receptor antagonists) as well as nutraceuticals (grape seed proanthocyanidin extract) could modulate RAGE expression and circulating sRAGE levels in cardiovascular disease states characterized by enhanced RAGE activation. Additionally, the production of genetically engineered sRAGE may hold promise for targeting the activation of RAGE by proinflammatory ligands in the setting of vascular inflammation. The present review considers current vascular drugs as modulators of the RAGE axis, and highlights future directions in the context of RAGE-directed therapy in cardiovascular disease.
...
PMID:Soluble RAGE-modulating drugs: state-of-the-art and future perspectives for targeting vascular inflammation. 1948 31

Sipahi et al. (2010) performed a meta-analysis of 5 clinical trials (n=68,402) of 3 Angiotensin II (AngII) receptor subtype AT-1 blockers (ARBs) in cardiovascular disease. It revealed excess new lung cancer diagnoses in the cohorts treated with an ARB and background therapy (0.9% vs. 0.7% in non-ARB control; RR: 1.25; CI: 1.05-1.49; p=0.01). The FDA responded with a larger meta-analysis of 31 clinical trials (n=155,816) of ARBs that found no evidence of any excess of site-specific cancer (lung, breast, prostate), solid/skin cancer or cancer death (FDA safety communication, 3 June 2011). The FDA then re-visited the 19 rodent carcinogenicity assays of 9 ARBs, starting with those for Losartan in 1994, for any evidence of dosage-related lung tumorigenicity in this class. Assays were performed in 5 strains of rats and 5 strains of wild-type and transgenic mice per protocols and dosages sanctioned by FDA's executive carcinogenicity assessment committee (eCAC). Duration was lifetime except for 26-week assays of azilsartan and olmesartan in transgenic Tg rasH2 mice, and an assay of olmesartan in p53(+/-) transgenic mice. The dosages provided exposures approximating, and in most cases up to 20-300times greater than, that in patients. Depending on strain, up to 35% of untreated mice spontaneously developed lung tumors. Regression analysis of placebo-corrected mouse lung tumor incidence collapsed across strains, gender, and ARBs vs. multiples of human exposure revealed no excess lung neoplasia. The R(2) of <0.001 reflected the virtually identical number of treated cohorts with more tumors than its control cohort vs. those with less. Regardless of strain, both control and medicated rats were essentially devoid of lung tumors in the lifetime trials. Accordingly, there was neither promotion of background lung tumors in the mouse, nor initiation of de novo lung tumors in the rat. The negative lung findings in the mouse Tg rasH2 strain are also noteworthy given that, historically, the most prevalent spontaneous tumors in 26week trials in that model are lung adenomas and carcinomas. The negative results of the 19, mostly lifetime, assays for cancer viewed en masse add to the results of the meta-analysis of the shorter clinical trials of ARBs that were benign regardless of statistical method used (random vs. fixed effect), comparator arm (with or without ACE-inhibitors) and major co-factors (smoking or cancer history).
...
PMID:An FDA overview of rodent carcinogenicity studies of angiotensin II AT-1 receptor blockers: pulmonary adenomas and carcinomas. 2522 63


<< Previous 1 2 3 Next >>

---