Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although increased deposition of collagen proteins has been described in cardiomyopathy, little is known of the temporal relationship between events in collagen gene transcription and the occurrence of cardiac fibrosis, the removal of collagen by matrix metalloproteinases (MMPs), or of the regulation of these events by angiotensin AT1 receptors in this disease. We sought to study steady-state collagen mRNA abundance and the deposition of specific collagen subtypes in right and left ventricular muscle of Syrian cardiomyopathic (CMP) hamsters at different stages of cardiomyopathy. Using zymography, we also investigated the gelatinolytic activities of different MMPs to gain some information about collagen removal in experimental hearts. Finally, we investigated the effect of AT1 receptor blockade (losartan) on collagen remodeling. We observed that the mRNA levels of types I and III collagens were significantly increased in all four experimental groups (35, 65, 120, and 200 day) in left ventricular tissue when compared to control (F1-beta strain) values. The mRNA levels of these collagen species in experimental right ventricular tissue samples were only elevated significantly in the 35 and 200 day experimental groups when compared to controls. Fibrillar collagen deposition was elevated in left and right ventricular CMP samples after a lag period from the occurrence of corresponding increases in mRNA abundance. Although 2-week losartan treatment of 65, 120 and 200 day experimental groups had no significant effect on left ventricular fibrillar collagen concentration or collagen mRNA abundance when compared to vehicle-infused CMP hamsters, AT1 receptor blockade was associated with complete regression of cardiac hypertrophy. Both MMP-1 (54 kDa band) and MMP-2 (58 and 62 kDa bands) activities were increased in left ventricular CMP tissues at 65, 120 and 200 days when compared to F1-beta controls. Losartan treatment was associated with significant attenuation of MMP activities in cardiomyopathic samples at 65 and 120 days. Thus, elevation of mRNA abundance of fibrillar collagen genes occurs at very early stages in this model of cardiomyopathy, and corresponding collagen proteins were subsequently deposited in the cardiac interstitium at later stages. As collagen concentration was significantly increased in later stages of cardiomyopathy studied herein (120 and 200 day groups), our data support the hypothesis that collagen synthesis exceeds the capacity of collagen removal during the progression of cardiomyopathy. Nevertheless, cardiac collagen remodeling may be facilitated by elevated MMP activity in cardiomyopathic stages in this experimental model, and we suggested that attenuation of MMP activity in the presence of losartan may be a cardioprotective mechanism of this agent.
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PMID:Cardiac collagen remodeling in the cardiomyopathic Syrian hamster and the effect of losartan. 923 38

The present study was undertaken to determine the effects of AT1 receptor blockade which occurred in response to losartan, on the extracellular matrix (ECM) degradation process in the Bio 14.6 (n = 12) and Bio 53.58 (n = 12) strains which are referred as models of hypertrophic and dilated cardiomyopathy, respectively. The administration of losartan (30 mg/kg/day) in hamsters from 10-20 weeks of age reduced the accumulation of the left ventricular collagen matrix in both of the Bio 14.6 and the Bio 53.58 strains. According to the RT-PCR, the levels of mRNA for matrix metalloproteinase (MMP) and the tissue inhibitor of MMP (TIMP) were examined. MMP-1, -2, -3, and -9 were more enhanced in both myopathic strains than in the control F1beta, strains. With losartan, the levels of MMP-1, -2, -9, TIMP-1 and -2 decreased in the both strains but those for MMP-3 did not in Bio 14.6 strains. TIMP-3 and -4 mRNA levels did not change in any of the experimental hamsters, whether treated or untreated with losartan. The Western blots also showed similar observations in the both strains as seen in mRNA expressions although MMP-2 in the Bio 53.58 strains did not differ between treated and untreated with losartan. Although losartan has an inhibitory effect on collagen accumulation in the development of cardiomyopathy, MMPs (-1, -2, -9) and TIMPs (-1, -2) seem to be susceptible to responding to losartan in Bio cardiomyopathic hamsters.
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PMID:Effects of losartan on the collagen degradative enzymes in hypertrophic and congestive types of cardiomyopathic hamsters. 1169 96

Although accumulating lines of evidence indicate the proangiogenic role of angiotensin II (Ang II), little is known about the molecular mechanisms associated with such an effect. This study aimed to identify molecular events involved in Ang II-induced angiogenesis in the Matrigel model in mice. C57Bl/6 female mice received a subcutaneous injection of either Matrigel or Matrigel with Ang II (10(-7) M) alone, with Ang II and an AT1 receptor antagonist (candesartan, 10(-6) M), or with Ang II and AT2 receptor antagonist (PD123319, 10(-6) M). After 14 days, angiogenesis was assessed in the Matrigel-plug by histological evaluation and cellular counting. Ang II increased by 1.9-fold the number of cells within the Matrigel (p < 0.01 versus control). Immunohistological analysis revealed the presence of macrophages, endothelial and smooth muscle cells, and the development of vascular-like structure. Such an angiogenic effect was associated with an increase in vascular endothelial growth factor (VEGF) (1.5-fold, p < 0.01), endothelial nitric oxide (eNOS) (1.7-fold, p < 0.01), and cyclooxygenase-2 (1.4-fold, p < 0.05) protein levels measured by Western blotting. Conversely, Ang II treatment did not affect MMP-9 and MMP-2 activity, assessed by zymography. Blockade of AT1 receptor completely prevented the Ang II-induced angiogenesis and protein regulations, whereas that of AT2 was ineffective. Administration of VEGF neutralizing antibody (2.5 microg ip twice a week) and cyclooxygenase-2 selective inhibitor (nimesulide, 30 mg/L) also hampered Ang II proangiogenic effect. In addition, Ang II-induced cell ingrowth was impaired by treatment with nitric oxide synthase inhibitor (L-NAME, 10 mg/kg/day) and in eNOS-deficient mice. Therefore, in an in vivo model, Ang II induced angiogenesis through AT1 receptor, which involved activation of VEGF/eNOS-related pathway and of the inflammatory process.
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PMID:Angiotensin II angiogenic effect in vivo involves vascular endothelial growth factor- and inflammation-related pathways. 1206 85

Activated matrix metalloproteinases (MMPs) in patients with acute coronary syndromes may contribute to plaque destabilization. Since reactive oxygen species (ROS) induce MMP-2 and angiotensin II (ANG II) enhances NADPH-oxidase-dependent ROS formation, we assessed whether ANG II induces MMP-2 in a NADPH-oxidase-dependent manner. MMP-2 mRNA expression and activity were analyzed in wildtype and p47phox-deficient (p47phox-/-) murine smooth muscle cells (SMC). To address a clinical implication, sections of human atherosclerotic arteries were stained for MMP-2, p47phox, ANG II, AT1-receptor, and alpha-smooth muscle cell actin (alpha-SMC actin). MMP-2 protein expression and activity from these arteries were compared to those without atherosclerosis. ANG II enhances mRNA synthesis and activity of MMP-2 in a p47phox-dependent manner. Immunohistochemical analyses revealed a co-localization of MMP-2 with p47phox, ANG II, AT1-receptor, and alpha-SMC actin. MMP-2 protein expression and gelatinolytic activity are increased in atherosclerotic arteries. Thus, activation of the renin-angiotensin system may contribute to plaque destabilization via ROS-dependent induction of MMP-2.
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PMID:Angiotensin II induces MMP-2 in a p47phox-dependent manner. 1567 Jul 68

Left ventricular dysfunction is associated with reperfusion injury occurring during open-heart surgery. There is an increased secretion of angiotensin II (Ang II) and increased matrix metalloproteinases (MMPs) activities associated with open-heart surgery that may affect the cardiac extracellular matrix (ECM). The goal of this study was to determine the effects of Ang II and selective angiotensin II receptor (AT1-R and AT2-R) blockers on the enzymatic activities of MMPs in primary adult murine cardiac fibroblasts (CF). Our hypothesis is that Aug II, with and without a selective receptor blocker, differentially affects CF MMPs activities. The CF were treated with Ang II (10(-6) M) and doses of AT1-R and AT2-R blockers (losartan and PD123319, respectively) at doses of 10(-7) to 10(-5) M for 48 hours. The Ang II-stimulated CF reduced collagenase activities by only 24% (p = 0.004); however, the MMP-2 and MMP-9 gelatinase activities were reduced by 42% and 39%, respectively (p = 0.022). The losartan dose dependently increased MMP-2 (p = 0.02) and MMP-9 (ns). PD123319 at 10(-5) M significantly reduced MMP-2 and MMP-9 activities compared with the Ang II group (p = 0.014 and p = 0.02, respectively). The doses of PD123319 at 10(-6) and 10(-7) M increased the MMP-2 and MMP-9 enzymatic activities significantly above the Ang II only group. Thus, Ang II and AT1-R and AT2-R differentially affect the collagenase and gelatinase MMPs activities released by cardiac fibroblasts.
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PMID:Effect of angiotensin II on primary cardiac fibroblast matrix metalloproteinase activities. 1763 35

Accumulation of specific deposits and extracellular molecules under the retinal pigment epithelium (RPE) has been previously observed in eyes with age-related macular degeneration (AMD) and may play a role in the pathogenesis of AMD. Even though age is the major determinant for developing AMD, clinical studies have revealed hypertension (HTN) as another systemic risk factor. Angiotensin II (Ang II) is considered the most important hormone associated with HTN. To evaluate the relationship of Ang II to AMD, we studied whether mouse RPE expresses functional Ang II receptor subtypes and whether HTN-induced Ang II regulates expression of these receptors as well as critical ECM molecules (MMP-2 and type IV collagen) involved in ECM turnover in RPE. We used 9-month-old C57BL/6 male mice infused with Ang II alone or Ang II in combination with the AT1 receptor antagonist candesartan or the AT2 receptor antagonist PD123319 for 4 weeks to determine whether HTN-associated Ang II was important for ECM regulation in RPE. We found that mouse RPE expressed both Ang II receptor subtypes at the mRNA and protein levels. Infusion with Ang II induced HTN and elevated plasma and ocular Ang II levels. Ang II also regulated AT1a and AT1b receptor mRNA expression, the intracellular concentration of calcium [Ca(2+)](i), MMP-2 activity, and type IV collagen accumulation. Concurrent administration of Ang II with the AT1 receptor blocker prevented the increase in blood pressure and rise in ocular Ang II levels, as well as the calcium and MMP-2 responses. In contrast, the type IV collagen response to Ang II was prevented by blockade of AT2 receptors, but not AT1 receptors. Plasma Ang II levels were not modified by the AT1 or AT2 receptor blockade. Since the effects of Ang II on MMP-2 and type IV collagen require inhibition of both Ang II receptor subtypes, these receptors may play a role as a potential therapeutic targets to prevent ECM turnover dysregulation in the RPE basement membrane, suggesting a pathogenic mechanism to explain the link between HTN and AMD.
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PMID:Angiotensin II-induced hypertension regulates AT1 receptor subtypes and extracellular matrix turnover in mouse retinal pigment epithelium. 1928 10

In the present study, we tested the hypothesis that angiotensin II (Ang II) has both direct (via AT1 receptors) and indirect (via sympathostimulator pathway) actions on the synthesis and activity of the enzymes involved in the extracellular matrix degradation in vivo. For this purpose, sympathectomy and blockade of the Ang II receptor AT1 were performed alone or in combination in normotensive rats. The mRNA of the plasminogen activator (t-PA) and its inhibitor (PAI-1), the mRNA, protein and activity of the matrix metalloproteinases MMP-2 and MMP-9 were examined by Q-RT-PCR, immunoblotting and zymographic methods in the left ventricle. t-PA and PAI-1 mRNA were decreased after sympathectomy and remained unchanged after AT1 receptors blockade. mRNA was increased for t-PA and decreased by similar degree for PAI-1 after double treatment. MMPs mRNA and protein levels were decreased either after sympathectomy or AT1 receptors blockade and an additive effect was acquired after double treatment. MMPs activity was decreased by similar degree in the three treated groups. Deducted interpretations from our experimental approach suggest that Ang II inhibits directly (via AT1 receptors) and indirectly (via sympathostimulator pathway) t-PA mRNA synthesis. It seems unable to influence directly PAI-1 mRNA, but stimulates indirectly PAI-1 mRNA synthesis. Ang II stimulates directly (via AT1 receptors) and indirectly (via sympathostimulator pathway) MMPs synthesis at both transcriptional and protein levels. The enzymatic activity of MMPs does not seem to be influenced directly by Ang II but it could be stimulated indirectly (via sympathostimulator pathway).
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PMID:Differential control of MMP and t-PA/PAI-1 expressions by sympathetic and renin-angiotensin systems in rat left ventricle. 1940 40

The number of patients suffering from heart failure is constantly increasing. One of its main causes is coronary artery disease, especially myocardial infarction. Progression of heart failure depends both on the extent of ischaemic injury and the course of subsequent adaptive processes. Genetic methods may help to find individuals at high risk of developing heart failure. There are multiple genes influencing circulatory system, some of their alleles may potentially affect progression of the disease. Among the most promising targets are genes of the renin-angiotensin-aldosterone system: insertion/deletion (L/D) polymorphism of angiotensin converting enzyme gene, polymorphisms of angiotensinogen, angiotensin receptors (AT1 and AT2) and aldosterone syntase genes. Other genetic factors, which may affect are different gene variants of adrenergic receptors (beta1, beta2, alpha2C), AMP deaminase-1, endothelin-1, endothelial nitric oxide syntase, precursors of natriuretic peptides and inflammatory factors (TNF-alpha, IL-6, MCP-1, TGF, MMP-2). Furthermore, the response to drugs may depend on genetic background, that is why pharmacogenetics creates new possibilities to tailor the best therapy for each patients with heart failure. Therefore research in the field of genetic factors affecting the development of heart failure has not only scientific, but also practical value.
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PMID:[Development of heart failure in the course of coronary artery disease--the role of genetic factors]. 2052 99

Melanoma is one of the most aggressive cancers of all solid tumors. The effect of angiotensin II on expression of three Matrix Metalloproteinases (MMPs) and Vascular Endothelial Growth Factor (VEGF) in B16F10 melanoma cells was evaluated. Also the blocking effect of losartan on angiotensin II induced effects was assessed. B16F10 murine melanoma cells were cultured in RPMI-1640 medium supplemented with 10% Fetal Bovine Serum (FBS) and 24 h prior to experiment the serum free medium was used. Angiotensin II (0 M, 10(-10) M, 10(-9) M or 10(-8) M) alone or in combination with Losartan (10(-6) M) in RPMI-1640 replaced the medium for experiments. After the incubation time (0, 1, 2, 6 and 12 h) cells were harvested using 0.05% (w/v) Trypsin and then recovered by centrifugation. The expression of MMP-2, MMP-13, MMP-9 and VEGF in B16F10 cell lysate was assessed by immunoblotting. Angiotensin II significantly enhanced the expression of MMP-2, MMP-13 and VEGF by concentrations as low as 0.1 nM. But angiotensin II could not stimulate any significant increase in MMP-9 expression by angiotensin II in B16F10 cells. Losartan abolished the enhancing effect of every concentration of angiotensin II on MMP-2, MMP-13 and VEGF expression completely and in all incubation times. As a result, angiotensin II through activation of AT1 receptors can stimulate the expression of MMP-2, MMP-13 and VEGF in B16F10 melanoma cells. This is an important conclusion because of the importance of these factors in melanoma invasiveness and the possible important role that angiotensin receptor blockers may play as cancer medications.
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PMID:AT1 receptors activation enhances the expression of MMP-2, MMP-13 and VEGF but not MMP-9 in B16F10 melanoma cells. 2259 Aug 32

Angiotensin II (Ang II) plays an important role in the maintenance of bone mass and integrity by activation of the mitogen-activated protein kinases (MAPKs) and by modulation of balance between resorption by osteoclasts and formation by osteoblasts. However, the role of Ang II in the turnover of extracellular matrix (ECM) in osteoid by osteoblasts remains unclear. Therefore, we examined the effect of Ang II on the expression of matrix metalloproteinases (MMPs), plasminogen activators (PAs), and their inhibitors [i.e., tissue inhibitors of metalloproteinases (TIMPs) and PA inhibitor-1 (PAI-1)] using osteoblastic ROS17/2.8 cells. Treatment with Ang II strikingly increased the expressions of MMP-3 and -13 and promoted cell proliferation associated with reduced alkaline phosphatase activity as well as enhanced phosphorylated expression of extracellular signal-regulated kinase (ERK)1/2, p38 MAPK, and stress-activated protein kinases/c-jun N-terminal kinases (SAPK/JNK) in ROS17/2.8 cells. However, Ang II had no effect on the expression of MMP-2, -9, -14, urokinase-type PA, tissue-type PA, TIMP-1, -2, -3, and PAI-1 in cells. Losartan (AT1 receptor blocker) blocked Ang II-induced expression of MMP-3 and -13, whereas PD123319 (AT2 receptor blocker) did not completely block these responses. Losartan also blocked the Ang II-induced phosphorylation of ERK1/2, p38 MAPK, and SAPK/JNK. MAPK kinase 1/2 inhibitor PD98059 and JNK inhibitor SP600125 suppressed Ang II-induced expression of MMP-3 and -13. These results suggested that Ang II stimulated the degradation process that occurs during ECM turnover in osteoid by increasing the production of MMP-3 and -13 through MAPK signaling pathways via the AT1 receptor in osteoblasts. Furthermore, our findings suggest that Ang II does not influence the plasminogen/plasmin pathway in osteoblasts.
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PMID:Angiotensin II induces the production of MMP-3 and MMP-13 through the MAPK signaling pathways via the AT(1) receptor in osteoblasts. 2327 13


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