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)

Hypertension induced in rats by suprarenal banding has a blood pressure elevating effect that is accompanied by the occurrence of cardiac hypertrophy and fibrosis. This phenomenon is already present at 2 weeks after banding and persists up to 1.5 years. The increase in cardiac weight is mostly due to the development of fibrosis, since myocytes are only slightly increased in size. The fibrotic tissue consists mainly of fibronectin and collagen and contains numerous cellular elements. The occurrence of fibrosis can be completely inhibited by the administration of the specific ACE inhibiting drug, ramipril, which indicated that angiotensin II may directly stimulate fibroblasts to produce fibronectin and collagen. The antifibrotic effect of ramipril was also present in a low dosage that did not lower blood pressure, confirming the hypothesis that angiotensin II has a direct effect on connective tissue cells and their ability to produce extracellular matrix proteins. The direct effect of the renin-angiotensin system on the activity of interstitial cells was further proven by molecular biology techniques showing an upregulation of transcription for collagen I and III which is prevented by ACE inhibition.
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PMID:Extracellular matrix deposition in hypertensive hearts antifibrotic effects of ramipril. 755 70

In arterial hypertension or congestive heart failure, myocardial fibrosis is associated with an activated renin-angiotensin-aldosterone system (RAAS). This reactive fibrosis presents as an excessive accumulation of fibrillar collagen within the normal connective tissue structures of the myocardium in either ventricle, irrespective of its haemodynamic load. It therefore would appear that circulating (hormonal) and not haemodynamic factors are responsible for this adverse fibrous tissue response. The cardiac fibroblast expresses mRNA for types I and III collagens, the major fibrillar collagens in the heart, and for collagenase or matrix metalloproteinase 1 (MMP 1), the key enzyme for interstitial collagen degradation. Therefore, adult rat cardiac fibroblasts were cultured to ascertain whether the RAAS effector hormones angiotensin II (Ang II) or aldosterone (Aldo) directly stimulate collagen synthesis or inhibit MMP 1 production. Collagen synthesis, determined by 3H-proline incorporation and MMP 1 activity determined by degradation of 14C-collagen, were measured under serum-free conditions in confluent, quiescent fibroblasts after 24 h incubation with Ang II or Aldo over a wide range of concentrations (10(-11) -10(-6) M). In addition, collagen synthesis was measured after incubation with the mineralocorticoid, dexoycorticosterone (DOC), or the prostaglandin, PGE2. Collagen synthesis, normalized per total protein synthesis, increased significantly in a dose-dependent manner after incubation with either mineralocorticoid hormone, Aldo or DOC, or after incubation with Ang II compared with untreated control cells. In contrast, collagen synthesis was significantly decreased with PGE2 treatment. This increase in collagen synthesis in Ang II or mineralocorticoid-stimulated fibroblasts could be completely abolished by Ang II type 1 or mineralocorticoid receptor antagonists, respectively. (ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hormonal regulation of cardiac fibroblast function. 755 72

Chronic cyclosporine (CsA) nephrotoxicity is a major complication of solid organ transplantation, and is characterized histologically by striped tubulointerstitial fibrosis, tubular atrophy, and hyalinization of the afferent arteriole, a highly specific finding in cyclosporine injury. The salt-depleted rat model of chronic cyclosporine nephropathy mimics these lesions in humans. We conducted sequential studies of this model in groups of pair fed rats (N = 6) treated with CsA (15 mg/kg, s.q.) or an equivalent dose of olive oil. Proliferation of tubular and interstitial cells was documented early in the medulla by day 5 (3.2 +/- 2.1 vs. 0.81 +/- 0.4 cells/HPF in CsA vs. control, P < 0.02), and was maximal in areas of interstitial fibrosis by day 35 (7.9 +/- 3.7 vs. 0.52 +/- 0.2 cells/HPF in CsA vs. control, P < 0.005). The interstitial fibrosis was associated with a significant macrophage influx by day 35 (13.9 +/- 3.5 vs. 1.5 +/- 0.32 cells/HPF, CsA vs. control, P < 0.005), which correlated with increased cortical tubular staining for the macrophage adhesion protein, osteopontin. Elevated serum creatinine correlated with interstitial fibrosis at day 35 (0.85 +/- 0.11 vs. 0.40 +/- 0.03 mg/dl Cr, CsA vs. control, P < 0.005) by linear regression (r = 0.9, P < 0.05). Medullary proliferation and interstitial fibrosis correlated with decreased tubular concentrating ability, and higher urinary volume. Cortical interstitial fibrosis was maximal at day 35 and was associated with an increase in type I and type IV collagen deposition, while tubular injury was associated with increased vimentin expression. Tubular interstitial cells also expressed increased vimentin early in the medulla (day 10) and later in the cortex. Both groups remained normotensive despite significantly elevated juxtaglomerular (JG) apparatus renin expression in CsA treated animals, implicating the intrarenal-renal renin-angiotensin system in this disease. We conclude that cyclosporine nephrotoxicity is associated with early tubular and interstitial cell proliferation, and a significant macrophage influx that precedes the development of cortical interstitial fibrosis and afferent arteriolar hyalinosis. These early cellular changes correlate with functional abnormalities including decreased creatinine clearance (CCr) and decreased medullary concentrating ability, which stabilized despite progressive fibrosis. These cellular events may be important in the pathogenesis of chronic CsA nephrotoxicity.
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PMID:Cellular proliferation and macrophage influx precede interstitial fibrosis in cyclosporine nephrotoxicity. 756 11

In chronic heart failure, the inter-relationship of the renin-angiotensin-aldosterone system (RAAS) and cardiac growth is of primary clinical interest. In the pressure or volume overloaded heart, hypertrophic growth of the myocardium includes the enlargement of cardiac myocytes--an adaptation governed by ventricular loading. Nonmyocyte cell growth involving cardiac fibroblast may also occur but not primarily regulated by the hemodynamic load. Cardiac fibroblast activation is responsible for the accumulation of fibrillar type I and type III collagens within the interstitium and adventitia of intramyocardial coronary arteries. In addition to relaxation abnormalities due to impairment of sarcoplasmic Ca(2+)-ATPase activity, this remodeling of the cardiac interstitium represents a major determinant of pathological hypertrophy in that it accounts for abnormal myocardial stiffness, leading to ventricular diastolic and systolic dysfunction and ultimately the appearance of symptomatic heart failure. In vivo and in vitro studies suggest that the effector hormones, angiotensin II and aldosterone, of the RAAS are primarily involved in regulating the structural remodeling of the myocardial collagen matrix. In cultured adult cardiac fibroblasts, angiotensin II and aldosterone have been shown to stimulate collagen synthesis while angiotensin II additionally inhibits matrix metalloproteinase 1 activity, which is the key enzyme for interstitial collagen degradation in the myocardium. These observations may serve as rationale why angiotensin converting enzyme inhibition or blockade of the RAAS represents such remedial therapy in congestive heart failure in patients with hypertensive heart disease, post-myocardial infarction or with dilated cardiomyopathy.
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PMID:Myocardial collagen matrix remodeling and congestive heart failure. 763 1

Unilateral ureteral obstruction (UUO) results in tubulointerstitial fibrosis of the obstructed kidney (OBK). In this study we report that a specific angiotensin II (Ang II) receptor antagonists, SC-51316, ameliorates the expansion of the renal cortical interstitium in the OBK of the rat at five days of UUO. This is similar to the effect of an angiotensin converting enzyme (ACE) inhibitor, enalapril. SC-51316 (20 mg/liter in the drinking water) or enalapril (200 mg/liter in the drinking water) was administered beginning 24 hours before UUO and continued through five days after UUO. The relative volume of the tubulointerstitium (Vv) was measured by a point-counting method, and monocyte/macrophage infiltration, alpha smooth muscle actin (alpha SMA), proliferating cell nuclear antigen (PCNA), and collagen type IV (collagen IV) protein deposition were examined histologically using specific antibodies. We also examined the mRNA levels of transforming growth factor beta 1 (TGF-beta 1) and collagen IV by reverse transcription polymerase chain reaction. In untreated rats with UUO, Vv was remarkably expanded; collagen IV and alpha SMA protein deposition in the interstitium and PCNA labeling of nuclei were increased. These changes were significantly ameliorated by administration of an ACE inhibitor or an Ang II receptor antagonist. A monocyte/macrophage infiltration was evident in the OBK of untreated or Ang II receptor antagonist treated rats but was greatly reduced in the OBK of rats given enalapril. Increased expression of TGF-beta 1 mRNA and collagen IV mRNA was blunted (40 to 75%) by the administration of Ang II receptor antagonist or enalapril. The Ang II receptor antagonist or the ACE inhibitor did not affect the contralateral kidney of rats with UUO or the control kidney of normal rats. This study indicates that the renin-angiotensin system has a major role in the pathogenesis of the tubulointerstitial fibrosis of obstructive nephropathy. The tubulointerstitial fibrosis of obstructive nephropathy is most likely mediated by an increased level of Ang II in renal tissue.
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PMID:Angiotensin II receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction. 763 58

To examine the effects of angiotensin-converting enzyme (ACE) inhibitor and aldosterone antagonist on myocardial collagen in the cardiomyopathic hamster, the collagen concentration was measured by determining the hydroxyproline concentration, and the ratio of type I to type III collagen (type I/III ratio) was measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Five-week-old Bio14.6 cardiomyopathic hamsters were treated with the ACE inhibitor captopril (20 mg/kg per day) or the aldosterone antagonist K-canrenoate (20 mg/kg per day) in drinking water for 20 weeks, and the collagen concentration and type I/III ratio at 25 weeks were compared with those in 25-week-old untreated Bio14.6 and normal F1b hamsters. The collagen concentration markedly increased and the type I/III ratio significantly decreased (ie, type III collagen dominant) in untreated Bio14.6 compared with F1b at 25 weeks. Captopril and K-canrenoate treatment significantly reduced the collagen concentration and reversed the changes in the type I/III ratio in cardiomyopathic hamster. These results suggest that ACE inhibitor and aldosterone antagonist improve myocardial collagen in the cardiomyopathic hamster, not only quantitatively but also qualitatively, and that the mechanism of this improvement may be related to the cardiac renin-angiotensin-aldosterone system.
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PMID:Effects of angiotensin-converting enzyme inhibitor and aldosterone antagonist on myocardial collagen in cardiomyopathic hamsters. 765 14

As in hypertension, the addition of a second active drug is believed to enhance treatment efficacy; however, the extent to which a combination of two low-dose drugs outperforms conventional monotherapy remains uncertain. Established treatments of angina comprises nitrates compounds, beta-blockers and calcium antagonists, which are often given in combination. Beta-blockers are major players in this field as they inhibit the tachycardia induced by nitrates and calcium antagonists; there is therefore a pathophysiological justification for their use in combination therapy, supported by repeated confirmation of positive clinical effect. The most widely chosen calcium antagonists are dihydropyridines; verapamil may impair conduction. However, it is not clear whether combination enhances the effects of the individual antianginal substances. Diuretics are for most clinicians the keystone treatment of heart failure; diuretics are often combined with other drugs, e.g. amiloride and spironolactone. The latter also have a beneficial effect on myocardial structure (myocardium/collagen ratio). ACE-inhibitors are of proven clinical efficacy, and, in addition, have a beneficial effect on survival. They combine well with diuretics: because the diuretic stimulates renin release, the ACE-inhibitor can be given at a lower dose (enhancement of effect). There are, however, certain drawbacks (hypotension, hyperkalemia with antialdosterones). The results of combining ACE-inhibitors with calcium antagonists and beta-blockers await investigation. The ISIS studies demonstrated the advantages of combining beta-blockers, thrombolysis and aspirin in acute infarction. ACE-inhibitors have recently been added to the regimen with a positive effect (extended survival), especially in the presence of a decreased ejection fraction (SAVE, AIRE, GISSI 3 and ISIS 4 studies).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Combination therapy in cardiovascular diseases other than hypertension]. 767 73

The Framingham heart study has shown that arterial hypertension is the major aetiological factor for the development of heart failure. In the presence of heart failure, various regulatory systems may be operative. These include the Frank-Starling mechanism, the neurohormonal system, regulation of cardiac growth and peripheral oxygen delivery. Recently, the interrelationship of the neuroendocrine system and cardiac growth has been examined. In the pressure or volume overloaded heart, growth of the myocardium involves the enlargement of cardiac myocytes, an adaptation governed by ventricular loading. Non-myocyte cell growth, including cardiac fibroblasts, may also occur. However, the haemodynamic load does not appear to be its major physiological stimulus. Cardiac fibroblast activation is responsible for the accumulation of type I and III collagens, the major fibrillar proteins of the myocardial collagen matrix, while vascular smooth muscle cell growth accounts for medial thickening of coronary resistance vessels. This structural remodelling of the cardiac interstitium represents a major determinant of pathological hypertrophy: it accounts for abnormal myocardial stiffness and impaired coronary reserve, thereby leading to ventricular diastolic and systolic dysfunction and ultimately the appearance of symptomatic heart failure. Several lines of evidence suggest that circulating and tissue renin-angiotensin-aldosterone systems are involved in the structural remodelling of the non-myocyte compartment, including the 'cardioprotective' effects of angiotensin converting enzyme (ACE) inhibition or the beneficial effects of anti-aldosterone treatment that were found to prevent myocardial fibrosis in renovascular hypertension due to unilateral renal ischaemia under experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of the structural remodelling of the myocardium: from hypertrophy to heart failure. 771 13

Extrahepatic synthesis and localization of angiotensinogen have been described in animals, thus establishing the tissue renin-angiotensin system. We examined angiotensinogen messenger RNA synthesis by northern blotting. It was detected not only in the liver, but also in both the atrial and ventricular heart tissues, suggesting that angiotensinogen is synthesized in the human heart. Immunohistochemical studies using a specific antibody to angiotensinogen revealed a stronger reaction in the endocardial layer of the human left ventricle, than in the epicardial layer, and intense immunoreactivity in the conduction system and right atrium. Furthermore, our experiments revealed a widespread immunopositive reaction for angiotensinogen in the left ventricle of diseased hearts. We examined the participation of the collagen in the occurrence and progression of cardiomyopathy. The acetic acid solubility of collagen and reducible crosslink decreased in cardiomyopathic hamsters as the fibrosis progressed, but was unchanged in controls. These findings indicate that in the early phase of cardiomyopathy the extracellular matrix of the myocardium is similar to immature tissues. In the later phase, the matrix resembles that of hard tissues, and is insoluble. Furthermore, we examined the relationship between angiotensin II and collagen synthesis. Basal collagen synthesis in cardiac fibroblasts from spontaneously hypertensive rats was 1.6-fold greater than that in Wistar-Kyoto rats. The responsiveness of collagen production to Ang II was significantly enhanced in SHR. This effect was angiotensin receptor-specific, because it was blocked by the competitive inhibitor. These results indicate angiotensin II may play an important role in collagen accumulation in hypertensive cardiac hypertrophy.
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PMID:Renin-angiotensin system in failing heart. 776 Mar 44

It is known that mechanical stress directly changes the conformation of the functional proteins, or directly activates enzymes such as phospholipase in the plasma membrane. The integrin-cytoskeleton complex may be an alternative candidate structure for a mechanoreceptor and a transducer. The cytoskeleton has been also shown to play an important role in secretion. Mechanical stress may stimulate the secretion of some cytokines or angiotensin II, which may generate multiple intracellular signals as a secondary event. External stimuli are generally transduced into the nucleus through the activation of protein kinase cascade. Stretching of cardiac myocytes stimulates the activity of PKC, Raf-1 kinase, MAP kinase kinase. MAP kinase and S6 kinase. In cardiac myocytes, mechanical stress directly induces gene expression as well as protein synthesis. Immediate early genes are first induced, and then fetal-type genes are reinduced. Both in hypertrophied hearts and in the experimental model of cardiac hypertrophy induced by pressure overload. Ca(2+)-ATPase content of cardiac myocytes is depressed. Reduced function of sarcoplasmic reticulum causes insufficient decrease of intracellular calcium in diastole and induces slowing of ventricular relaxation. In the interstitium of pressure overloaded hearts, the accumulation of collagen fiber is increased. The abnormal deposit leads to increased chamber stiffness and diastolic dysfunction. Furthermore, TGF-beta and tissue renin-angiotensin system are up-regulated in pressure overloaded hearts, both of which accelerate the interstitial fibrosis.
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PMID:Interaction of cardiac myocytes and non-myocytes in mechanical stress-induced hypertrophy. 777 62


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