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)

Smooth muscle cell proliferation and formation of extracellular matrix in the intima of muscular arteries after vascular injury can lead to severe intimal hyperplasia and stenosis. Cilazapril reduces intimal hyperplasia induced by balloon catheterization of the rat carotid artery by 80%, and significantly decreases the surface area covered by proliferative lesions. We investigated the effects of angiotensin II (A II) on SMC proliferation in cell culture and A-II induction of selected growth factor or growth-related genes in SMC in culture: PDGF A chain, TGF-beta, thrombospondin, c-myc and c-fos, and compared the influence of cilazapril on these responses to A II. A-II induced SMC proliferation, stimulated mRNAs for c-myc and c-fos after 30 min, and stimulated mRNAs for PDGF A chain, TGF-beta, and thrombospondin somewhat later. The ACE inhibitor did not have detectable independent effects on the A-II induced proliferation or gene expression. Thus, these data support the conclusion that cilazapril suppresses SMC proliferation in vivo through the block of conversion of A I to A II, and that A II has a critical and central role in the control of the proliferative response after balloon catheter-induced vascular injury.
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PMID:Cilazapril suppresses myointimal proliferation after vascular injury: effects on growth factor induction in vascular smooth muscle cells. 182 85

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

Both angiotensin II and TGF-beta are key mediators of glomerular and tubulointerstitial injury and fibrosis in progressive kidney diseases. It was thought that angiotensin II damages the kidney by increasing glomerular filtration pressure, whereas autocrine TGF-beta overexpression occurs from unidentified mechanisms. Recent studies reveal that angiotensin II is a potent inducer of TGF-beta synthesis in a variety of cells and that this mechanism exerts important biological effects including extracellular matrix accumulation, cell proliferation, and hypertrophy. Because these studies were performed in vitro, there is clear evidence that the biological effects were observed independently of the vasoconstrictive properties of angiotensin II. Although it is difficult to study angiotensin II-mediated effects in vivo without influencing systemic and glomerular blood pressure, further studies are needed to evaluate the ability of ACE-inhibitors and angiotensin II receptor blockers to suppress TGF-beta overexpression in selected models of chronic progressive kidney disease.
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PMID:Transforming growth factor-beta and angiotensin II: the missing link from glomerular hyperfiltration to glomerulosclerosis? 777 69

The in vivo effects of alacepril (1-[(S)-3-acetylthio-2-methylpropanoyl]- L-prolyl-L-phenylalanine), an angiotensin converting enzyme inhibitor, and SC-52458 (5-[(3,5-dibutyl-1H-1,2,4-triazol-1- yl)methyl]-2-[2-(1H-tetrazol-5-ylphenyl)]pyridine), an angiotensin AT1 receptor antagonist, were examined on the cardiac and aortic gene expressions of extracellular matrices and TGF-beta 1 in young spontaneously hypertensive rats (SHR). In SHR, types I and III collagen mRNAs were increased in the left ventricle, and in contrast, fibronectin, collagen IV, and transforming growth factor-beta 1 (TGF-beta 1) mRNAs were increased in aorta, compared with those in Wistar-Kyoto rats. All the enhanced mRNAs in both organs in SHR were significantly inhibited by the short-term treatment with the above two drugs. Thus, angiotensin AT1 receptor may play an important role in the regulation of extracellular matrices and TGF-beta 1 expressions in SHR.
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PMID:Role of angiotensin II in extracellular matrix and transforming growth factor-beta 1 expression in hypertensive rats. 782 53

Understanding the mechanisms of tubular hypertrophy is important because these cells simply represent the bulk of the nephron, and there is a convincing link between early tubular enlargement and the progression of renal disease. It seems reasonable to assume that cytokines and polypeptide growth factors including inhibitory factors such as TGF-beta induce in concert, rather than as single factors, tubular hypertrophy. The important observations that the activation of the intrarenal renin-angiotensin axis is altered in situations associated with renal growth, and that ACE inhibitors abolish compensatory hypertrophy in many models provided for us a basis for investigating the growth effects of ANG-II on cultured proximal tubular cells. ANG-II induces, as a single factor, tubular hypertrophy in vitro, and this growth effect has been studied in detail on a molecular levels. Endogenous induction of TGF-beta by ANG-II is important in the peptide-mediated hypertrophy. While some genes induced by ANG-II, such as immediate early genes, are engaged as part of a generalized activation of the nucleus, the hypertrophic effects may be mediated by a set of novel genes which may be part of an identifiable genetic program causing tubular enlargement. The identification of hypertrophy genes may offer new insight into the modulation of cytoplasmic enlargement and its interface with elements that control the cell cycle and may provide a tool for further therapeutic interventions.
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PMID:Regulating factors of renal tubular hypertrophy. 830 51

We studied the effect of the angiotensin converting enzyme (ACE) inhibitor, quinapril, on the clinical and morphological lesions of a normotensive model of immune complex nephritis. Untreated rats developed massive nephrotic syndrome, intense cell proliferation and glomerular and tubulointerstitial lesions. In the renal cortex of nephritic rats there was a significant increase in gene expression of TGF-beta 1, fibronectin and collagens, and ACE activity. Systolic blood pressure remained normal with progression of the disease. Administration of quinapril for three weeks to animals with glomerular lesions (proteinuria 20 to 50 mg/day) avoided the development of intense proteinuria (79 +/- 28 vs. 589 +/- 73 mg/day, P < 0.001) and decreased cell proliferation, glomerulosclerosis, tubulointerstitial lesions, and inflammatory infiltrates. Cortical gene expression of TGF-beta 1 and matrix proteins was also diminished. ACE activity was inhibited by 68% in renal cortex. These results show that quinapril administration to normotensive rats with immune complex nephritis decreases proteinuria and glomerular and tubulointerstitial lesions, probably modulating the local angiotensin II generation and its effects on cell growth, TGF beta and matrix protein synthesis.
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PMID:ACE inhibition reduces proteinuria, glomerular lesions and extracellular matrix production in a normotensive rat model of immune complex nephritis. 858 37

Spontaneously hypertensive rats (SHR) of advanced age exhibit depressed myocardial contractile function and ventricular fibrosis, as stable compensated hypertrophy progresses to heart failure. Transition to heart failure in SHR aged 18-24 months was characterized by impaired left ventricular (LV) function, ventricular dilatation, and reduced ejection fraction without an increase in LV mass. Studies of papillary muscles from SHR with failing hearts (SHR-F), SHR without failure (SHR-NF), and age-matched Wistar Kyoto (WKY) rats allowed examination of changes in the mechanical properties of myocardium during the transition to heart failure. Papillary muscles of SHR-F exhibited increased fibrosis, impaired contraction, and decreased myocyte fractional area. These findings in papillary muscles were correlated with a higher concentration of hydroxyproline and increased histological evidence of fibrosis in the LV free wall. While a depression in active tension accompanied these structural alterations in papillary muscles, it was not evident when active tension was normalized to myocyte fractional area. Together, these data suggest that individual myocyte function may be preserved but that myocyte loss and replacement by extracellular matrix contribute substantially to the decrement in active tension. An absent or negative inotropic response to isoproterenol is observed in SHR-F and SHR-NF papillary muscles and may result in part from age-related alterations in beta-adrenergic receptor dynamics and a shift from alpha- to beta-myosin heavy chain (MHC) protein. During the transition to failure, ventricles of SHR exhibit a marked increase in collagen and fibronectin mRNA levels, suggesting that an increase in the expression of specific extracellular matrix genes may contribute to fibrosis, tissue stiffness, and impaired function. Transforming growth factor-beta 1 (TGF-beta 1) mRNA levels also increase in SHR-F, consistent with the concept that TGF-beta 1 plays a key regulatory role in remodelling of the extracellular matrix gene during the transition to failure. The renin-angiotensin-aldosterone system is also implicated in the transition to failure: SHR treated with the angiotensin converting enzyme inhibitor captopril starting at 12 months of age did not develop heart failure during the 18-24 month observation period. Captopril treatment that was initiated after rats were identified with evidence of failure led to a reappearance of alpha-MHC mRNA but did not improve papillary muscle function. Research opportunities include investigation of apoptosis as a mechanism of cell loss, delineation of the regulatory roles of TGF-beta 1 and the renin-angiotensin-aldosterone system in matrix accumulation, and studies of proteinase cascades that regulate matrix remodelling.
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PMID:The ageing spontaneously hypertensive rat as a model of the transition from stable compensated hypertrophy to heart failure. 868 57

Tubulointerstitial fibrosis in unilateral ureteral obstruction (UUO) is driven by increased levels of angiotensin II (Ang II). In this study, we examined the time course of the fibrotic process in rats with UUO and explored the effect of delayed administration of an angiotensin converting enzyme (ACE) inhibitor, enalapril, on the tubulo-interstitial fibrosis of obstructive uropathy. Rats were sacrificed at 3, 5, 8, or 10 days after UUO was initiated. Some rats did not receive treatment, whereas others were treated with enalapril from day 4 to day 8 or from day 6 to day 10 after the onset of UUO. The levels of mRNA for transforming growth factor beta 1 (TGF-beta 1), collagen type IV (collagen IV), and tissue inhibitor of metalloproteinase (TIMP-1) were measured at each time point by reverse transcription-polymerase chain reaction (RT-PCR). The relative volume of the tubulointerstitium (Vv) was measured by a point-counting method. Monocyte/macrophage infiltration and collagen IV protein deposition were examined histologically using specific antibodies. There were significant increases in TGF-beta 1, TIMP-1, and collagen IV mRNAs in the obstructed kidney. Treatment with enalapril on day 4 through day 8 or on day 6 through day 10 significantly reduced the elevated mRNA levels of these compounds in the obstructed kidney. Histological studies showed augmented Vv, monocyte/macrophage infiltration, interstitial alpha-smooth muscle actin expression, and collagen IV protein deposition on days 3, 5, 8, or 10 of UUO; enalapril treatment from day 4 to 8 or from day 6 to 10 halted and to an extent reversed these increases. These data suggest that enalapril administration after several days of UUO is an effective means of preventing the progression of tubulointerstitial fibrosis of obstructive uropathy.
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PMID:Delayed treatment with enalapril halts tubulointerstitial fibrosis in rats with obstructive nephropathy. 869 32

Although rapid growth of the heart during early postnatal development ceases with maturation of the organism, the potential for cardiomyocyte growth is not lost and may be observed even in senescent hearts. Rapid developmental heart growth is accompanied by a proportional growth of capillaries but not always of larger vessels, and thus coronary vascular resistance gradually increases. Growth of adult hearts can be enhanced by thyroid hormones, catecholamines and the renin-angiotensin system hormones, but these do not always stimulate growth of coronary vessels. Likewise, chronic exposure to hypoxia leads to growth, mainly of the right ventricle and its vessels but without vascular growth elsewhere in the heart. On the other hand, ischaemia is a potent stimulus for the release of various growth factors involved in the development of collateral circulation. Heart hypertrophy develops in response to training, pressure or volume overload. Training usually leads to growth of larger coronary vessels but little growth of capillaries, except in young animals. However, growth of the capillary bed, but not the resistance vasculature capacity, can be induced by either increased coronary blood flow, bradycardia (electrically or pharmacologically induced) or increased inotropism, all of which are involved in the training stimulus. Thus, what actually promotes growth of larger vessels as opposed to capillaries in training is unclear. Pressure overload hypertrophy is mediated by both the renin-angiotensin system and the response of cardiomyocytes to stretch; both lead to activation of early oncogenes (c-fos, c-jun, c-myc) and angiotensin II activates several protein kinases involved in cell growth. In this condition, growth of larger vessels is inadequate, although some capillary growth may occur. Volume overload leads to cardiomyocyte hypertrophy and hyperplasia and some increase in vascular supply. Deficits in capillary supply in pressure or volume overload hypertrophy can be reversed by chronic administration of ACE inhibitors, dipyridamole, the bradycardic drug alinidine or pacing-induced bradycardia respectively, but in neither case is training effective. Mechanical and humoral factors are involved in growth of cardiomyocytes and vessels. For cardiomyocytes, stretch is most important, activating oncogenes, protein kinases and possibly the inositol phosphate pathway, but not ion channels, with regulation by the balance of angiotensin II, TGF-beta 1 and IGF-1, but not FGFs. For vessels, growth is stimulated by stretch and shear stress, possibly with involvement of VEGF. Increased shear stress disrupts the glycocalyx on the luminal side of vessels and releases plasminogen activator and metalloproteinases which disrupt the basement membrane and enable endothelial cell migration and proliferation. It also causes rearrangement of the endothelial cytoskeleton and transmission of mechanical signals to the abluminal side disturbing extracellular matrix and causing distortion of capillary basement membrane. Stretch acting from the abluminal side has a similar effect resulting also in basement membrane disruption and endothelial cell proliferation.
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PMID:Postnatal growth of the heart and its blood vessels. 869 52

Vascular remodeling in adult human elastic pulmonary arteries is characterized by diffuse neointimal lesions containing smooth muscle cells expressing extracellular matrix genes. Recent studies suggest vascular injury is needed to initiate remodeling and that growth factor mediators participate in the repair response. However, because neointimal formation is only observed in patients with pulmonary artery blood pressures approaching systemic levels, it has been hypothesized that systemic-like hemodynamic conditions are also necessary. To test that hypothesis, subclavian-pulmonary artery anastomoses were created in Sprague-Dawley rats under three different experimental conditions: no accompanying injury, or after monocrotaline or balloon endarterectomy injury. Pulmonary vascular remodeling was not induced by the subclavian-pulmonary artery anastomosis alone. A non-neointimal pattern of remodeling after mild monocrotaline-induced injury was converted into a neointimal pattern in the presence of the anastomosis. Neointima was also observed after severe, balloon endarterectomy-induced injury even in the absence of anastomosis. Tropoelastin, type I procollagen and TGF-beta gene expression, and angiotensin converting enzyme immunoreactivity, was confined to the neointima resembling the pattern of gene expression and immunoreactivity in human hypertensive elastic pulmonary artery neointimal lesions. These observations introduce the concepts that the type of injury and the associated hemodynamic conditions can modify the elastic pulmonary artery response to injury.
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PMID:The role of vascular injury and hemodynamics in rat pulmonary artery remodeling. 875 54


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