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)

For a long time chronic heart failure was seen as a purely myocardial problem, which is characterized by symptoms in consequence of an impaired contractility. Later on it became apparent that chronic heart failure is at least in part characterized by activation of the neuroendocrine system, in particular the sympathetic nervous system and the renin-angiotensin-aldosterone system. This neuroendocrine system is an important system that is not only responsible for symptoms but probably very important for the development and progression of heart failure and therefore relevant to the prognosis of these patients. Apart from this neuroendocrine activation heart failure is characterized by an inflammatory component. The mechanisms of inflammation seem to play an important role in the process of left ventricular remodeling including structural and functional changes of the myocardium which are not only in part responsible for the development of symptoms but also for the progression of disease. It turns out that pathophysiological consequences of activated inflammation are deleterious in the long term, but may provide transient protective effects in the acute stage of ischemia. Regarding clinical trials it can be assumed that general inhibition of the inflammation process by inhibition of tumor necrosis factor-(TNF-)alpha does not necessarily exert favorable effects.
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PMID:[Mechanisms of inflammation in heart failure]. 1559 75

We recently demonstrated that both lisinopril and candesartan, an angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor blocker, respectively, attenuate pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori (WBN/Kob) rats. The purpose of the present study was to assess whether combination therapy with low doses of both, ineffective when given alone, might synergistically exert protective effects. Lisinopril, candesartan, or a combination of both in drinking water was administered to 10-week-old male WBN/Kob rats for 10 weeks. Parameters of inflammation and fibrosis, positive immunostaining for alpha-smooth muscle actin, and gene expression of cytokine and growth factors were assessed, as well as circulating renin-angiotensin system components. Dose-dependent effects of combination therapy were also investigated. Only combination therapy attenuated gross alterations in the pancreas, as quantitatively confirmed by increases in pancreatic weights and decreases in myeloperoxidase activity, hydroxyproline content, histologic scores, relative fibrosis area, and relative area of alpha-smooth muscle actin-positive cells. Combination therapy suppressed up-regulation of tumor necrosis factor-alpha, platelet-derived growth factor-receptor beta, and transforming growth factor-beta1 mRNA in the pancreas. Dose dependence of combination therapy was recognized with reference to improvement in these parameters. The conclusions are that combination therapy synergistically alleviated pancreatic inflammation and fibrosis in male WBN/Kob rats. This effect may be related to suppression of tumor necrosis factor-alpha, platelet-derived growth factor-receptor beta, and transforming growth factor-beta1 mRNA. Compared with the either therapy alone, combination therapy with an angiotensin-converting enzyme inhibitor and an angiotensin II type 1 receptor blocker may be more beneficial for treating chronic pancreatitis.
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PMID:Combination therapy with an angiotensin-converting enzyme inhibitor and an angiotensin II receptor blocker synergistically suppresses chronic pancreatitis in rats. 1560 84

Acute renal failure (ARF) affects about 10% of severely ill neonates. Recent studies have shown that genetic polymorphisms of proteins that play a role in neonatal physiology may contribute to individual susceptibility to both ARF and its risk factors. Our review summarizes the data collected to date. Studies have shown that the risk of preterm neonates for ARF is directly associated with a combination of high tumor necrosis factor-alpha producer and low interleukin-6 producer genotypes, as well as with low heat shock protein 72 producer genotype. Premature birth is itself the most important risk factor for a number of complications, including ARF, and recent studies have also shown an association between several maternal and fetal cytokine genetic polymorphisms and increased inflammatory response in preterm neonates. These polymorphisms could also be associated with increased risk for disorders such as sepsis and necrotizing enterocolitis, which lead to renal hypoperfusion and ARF. Genetic polymorphisms of the renin-angiotensin-aldosterone system have not been shown to directly influence risk for ARF. They may, however, be associated with patent ductus arteriosus, poor postnatal adaptation, and heart failure, which are all prevalent risk factors for ARF.
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PMID:Genetic polymorphisms and risk for acute renal failure in preterm neonates. 1562 70

A bidirectional relationship exists between depression and cardiovascular disease. Patients with major depression are more likely to develop cardiac events, and patients with myocardial infarction and heart failure are more likely to develop depression. A feature common to both clinical syndromes is activation of proinflammatory cytokines and stress hormones, including the hypothalamic-pituitary-adrenal axis and the renin-angiotensin-aldosterone system. In the present study we examined the hypothesis that exposure to chronic mild stress (CMS), an experimental model of depression that induces anhedonia in rats, is sufficient to activate the production of proinflammatory cytokines and stress hormones that are detrimental to the heart and vascular system. Four weeks of exposure of male, Sprague-Dawley rats to mild unpredictable environmental stressors resulted in anhedonia which was operationally defined as a reduction in sucrose intake without a concomitant effect on water intake. Humoral assays indicated increased plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), plasma renin activity, aldosterone, and corticosterone in the CMS exposed rats. Tissue TNF-alpha and IL-1beta were increased in the hypothalamus, and TNF-alpha was increased in the pituitary gland. These humoral responses to CMS, associated with anhedonia as an index of depression in the rat, are likely to be associated with neurohumoral mechanisms that may contribute to adverse cardiac events. The findings provide a basis for examining more directly the interactions among the central, endocrine, and immune systems in depression associated with heart disease.
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PMID:Neuroendocrine and cytokine profile of chronic mild stress-induced anhedonia. 1588 45

We tested whether or not complement activation participates in angiotensin (Ang) II-induced vasculopathy. We used double transgenic rats harboring human renin and angiotensinogen genes (dTGR) with or without losartan or the human renin inhibitor aliskiren. Sprague-Dawley (SD) rats were controls. DTGR had increased blood pressure at week 5 that increased further by week 7. Albuminuria was absent at week 5 but increased markedly in weeks 6 and 7. C-reactive protein (CRP) elevation, macrophages, T cells, tumor necrosis factor (TNF)-alpha, C1q, C3, C3c, and C5b-9 expression preceded albuminuria. C1q, C3, C3c, and C5b-9 were observed in the dTGR vessel media. C5b-9 colocalized with interleukin (IL)-6. Losartan and aliskiren reduced albuminuria and complement expression. We also studied vascular smooth muscle cells (VSMC) from dTGR compared VSMC from SD. C3 and IL-6 mRNA were analyzed after Ang II, TNF-alpha, and CRP stimulation. VSMC from dTGR showed increased proliferation and C3 expression compared with SD. Ang II did not induce C3 mRNA in either VSMC type. However, TNF-alpha and CRP induced C3 mRNA slightly in SD VSMC but markedly in dTGR VSMC, whereas IL-6 induction was similar in both. Thus, complement activation and cell infiltration occurred before the onset of albuminuria in Ang II-mediated renal damage. TNF-alpha and CRP played a major role in C3 activation. VSMC from dTGR are more sensitive for C3 activation. Our data show that, in this Ang II-induced model, complement activation is a major participant and suggest that TNF-alpha and CRP may play a role in its induction.
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PMID:Complement activation in angiotensin II-induced organ damage. 1610 17

We have reported that tumor necrosis factor (TNF)-alpha in skeletal muscle is one of the determinants of insulin resistance and that the renin-angiotensin system may be related to the regulation of TNF-a in skeletal muscle. Recent studies have suggested the involvement of cyclic adenosine monophosphate (cAMP) in the regulation of TNF-a in vascular smooth muscle cells or monocytes. The aim of this study was to determine the relationship between cAMP and TNF-a in skeletal muscle in connection with the renin-angiotensin system. Six-week-old male Sprague-Dawley rats were fed either normal rat chow or fructose-rich chow for 6 weeks. For the last 2 weeks of a 6-week period, the rats were treated with a vehicle or with an angiotensin II type 1 receptor antagonist (olmesartan medoxomil, 0.1 mg/kg/day). TNF-alpha levels in the soleus muscle were significantly higher and cAMP levels in the soleus muscle were significantly lower in fructose-fed rats than in control rats. Olmesartan increased cAMP and reduced TNF-a simultaneously in fructose-fed rats. There was a significant negative correlation between levels of cAMP and TNF-alpha. Moreover, a cAMP analogue reduced TNF-a levels in the soleus muscle. These results indicate that the increase in TNF-alpha via suppression of cAMP may affect the induction of insulin resistance. In addition, the facts that olmesartan increased cAMP and decreased TNF-alpha suggest that a part of the TNF-alpha regulation by angiotensin II might consist of modulation of cAMP through Gi protein activation in skeletal muscle.
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PMID:Olmesartan ameliorates insulin sensitivity by modulating tumor necrosis factor-alpha and cyclic AMP in skeletal muscle. 1641 41

Proteinuria (albuminuria) reflects dysfunction of the glomerular permeability barrier in which inflammatory cytokines play a key role. Pentoxifylline (PTX) is a phosphodiesterase inhibitor that possesses potent anti-inflammatory and immunomudulatory effects. This study evaluated the effectiveness of PTX to reduce proteinuria and inflammatory mediators in patients with proteinuric primary glomerular diseases. Seventeen patients with primary glomerular diseases, a persistent spot proteinuria exceeding 1.5 g/g creatinine (Cr) and a glomerular filtration rate between 24 and 115 ml/min/1.73 m(2) were treated with PTX 400 mg twice daily for 6 months. Before and after the treatment, serum Cr, plasma renin activity and aldosterone concentrations, plasma and urinary tumor necrosis factor (TNF)-alpha, interleukin-1beta and monocyte chemoattractant protein (MCP)-1, as well as urinary protein and Cr were measured. PTX significantly reduced urinary protein excretion, along with an increase of serum albumin. A significant correlation existed between the basal urinary protein/Cr and the basal urinary MCP-1/Cr ratios. PTX lowered the urinary MCP-1/Cr ratio, and the percent reduction of urinary protein/Cr ratio correlated directly with the precent decrease of urinary MCP-1/Cr ratio after PTX treatment. There was no significant change in blood pressure, renal function, biochemical parameters, plasma renin activity and aldosterone concentrations, or plasma TNF-alpha and MCP-1 levels during the study. In conclusion, administration of PTX 800 mg per day is safe and effective for reducing proteinuria in patients with proteinuric primary glomerular diseases. This beneficial effect occurs in close association with a reduction of urinary MCP-1 excretion.
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PMID:Pentoxifylline ameliorates proteinuria through suppression of renal monocyte chemoattractant protein-1 in patients with proteinuric primary glomerular diseases. 1654 Oct 21

We measured serum interleukin-2 receptor (sIL-2R), tumor necrosis factor-a (TNF-a), Fas receptor (sFas), nitric oxide (NO), and angiotensin converting enzyme (ACE) activity in 45 patients with congestive heart failure (CHF) of different etiologies. The relatioship between these bioindices and the severity of heart failure was analysed. Patients were classified according to the etiology of heart failure into: 15 patients with rheumatic valvular heart disease (RHD), 17 with ischemic heart disease (IHD) and 13 with idiopathic dilated cardiomyopathy (DCM). Patients were further classified according to severity of CHF following the New York Heart Association classification (NYHA) into: NYHA class II (n= 7), NYHA class III (n=20) and NYHA class IV (n=18). Eighteen healthy subjects were included as controls. Serum sIL-2R, TNF-alpha and sFas levels were determined by ELISA while serum NO and ACE levels were measured by colorimetric methods. Doppler Echocardiography was performed for all participants. Levels of sIL-2R, TNF-alpha, sFas, NO, and ACE were significantly higher in CHF patients than controls. Levels of the bioindices varied according to the CHF etiology. TNF-a level was the only one that had significant differences among different subgroups (RHD, IHD and DCM). The levels of sIL-2R, TNF-alpha, NO and sFas in patients with NYHA class IV were significantly higher than class II or III. Moreover, sIL-2R, TNF-alpha and NO levels were significantly higher in patients with diastolic dysfunction than patients with normal diastolic function. A significant positive correlations were found between sFas and both TNF-alpha and sIL-2R and between TNF-alpha and both NO and diastolic function. In addition, significant positive correlations were found between TNF-alpha and sIL-2R in both IHD and RHD patients and between sIL-2R and both ACE in IHD patients and diastolic function in DCM patients. It is concluded that a relationship exists between immune system activation, apoptosis and renin- angiotensin system in CHF and this may play a significant role in the pathophysiology and prognosis of the disease.
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PMID:Proinflammatory cytokines, soluble Fas receptor, nitric oxide and angiotensin converting enzyme in congestive heart failure. 1673 38

This study compares the effect of two different strategies to inhibit the renin-angiotensin system in the setting of acute myocardial infarction (MI). Male Wistar rats were treated with placebo, the angiotensin-converting enzyme (ACE) inhibitor ramipril (1 mg/kg/day), or the AT1 receptor antagonist, olmesartan (1 mg/kg/day), both initiated 1 week before induction of MI and continued for 6 weeks after MI. The inflammatory reaction in the heart was investigated 7 days post-MI by determination of macrophage infiltration and the expression of tumor necrosis factor (TNF-alpha), interleukin (IL)-1beta and IL-6 at mRNA and protein levels. Six weeks post-MI, cardiac function was measured following chronic implantation of catheters in the LV and femoral artery, and cardiac morphology and coronary structure were investigated in picrosirius-red stained hearts. In placebo-treated rats, macrophage infiltration was accompanied by upregulation of IL-1beta and IL-6 mRNA in the peri-infarct zone. TNF-alpha and IL-1beta mRNA and protein were also upregulated in the non-infarcted myocardium. Whereas both treatment regimes significantly reduced IL-6 upregulation, olmesartan additionally reduced macrophage infiltration and IL-1beta expression. Six weeks post-MI, placebo-treated MI animals developed an impaired cardiac function with structural remodeling of the myocardium and coronaries. While olmesartan and ramipril both improved cardiac function and reduced infarct size and myocardial/coronary remodeling, olmesartan was more effective not only in increasing vascular perimeter, inner vascular diameter and septal thickness but also in lowering media thickness of coronary arteries, inner left ventricular diameter, left ventricular circumference and left ventricular end-diastolic pressure than ramipril. Thus, following MI the AT1 receptor blocker, olmesartan, attenuated cardiac inflammatory reactions and protected myocardial/coronary structure and function of the failing heart proving to be of similar, in some cases superior effectiveness in this respect than the ACE inhibitor, ramipril.
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PMID:Differential effects of olmesartan and ramipril on inflammatory response after myocardial infarction in rats. 1675 75

Inflammation is a key mechanism in the initiation, progression, and clinical sequelae of cardiovascular diseases (CVDs), including atherosclerosis, nephropathy, and cardiomyopathy. Angiotensin II, the major effector peptide of the renin-angiotensin-aldosterone system (RAAS), plays a significant role in the advent and perpetuation of these inflammatory diseases, most notably in atherogenesis. Consequently, suppression of the influence of angiotensin II by angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may reduce or potentially reverse atherosclerosis and other inflammation-associated CVDs. Angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors exert anti-inflammatory actions and prevent or reduce the development of atherosclerosis in animal models. Clinically, RAAS suppression reduces common carotid and femoral artery intima-media thickness, thus indicating moderation of the vascular disease process. These clinical benefits likely involve restraint of the deleterious effects of angiotensin II in addition to, or independent of, lowering blood pressure. Increasing evidence that the detection and monitoring of vascular inflammation are important tools in the management of atherosclerosis also implicates the RAAS in this pathogenic process. Inflammatory molecules such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, tumor necrosis factor-alpha, and C-reactive protein have potential diagnostic and prognostic values in CVD and are modified by angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. Monitoring these markers may be crucial for determining which agents, or combinations of agents, will result in the most clinically beneficial outcomes for patients. Large-scale trials are still required to determine the effects of the long-term suppression of inflammation on CVDs through the use of RAAS modulating agents, as well as to determine how closely markers of inflammatory activity may correlate with CVD outcomes.
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PMID:Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease. 1712 70


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