Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was designed to assess whether a specific endothelin A (ETA) receptor antagonist, FR139317, affects the progression of lupus nephritis and affects transcription of mRNA for extracellular matrix (ECM) components, metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP)-1, and accumulation of ECM proteins in the renal cortex of NZB/W F1 mice. mRNA levels for alpha 1(I), alpha 1(III), alpha 1(IV) collagen chains, laminin B1 and B2 chains, heparan sulfate proteoglycan (HSPG), MMP-1, -2, -3, and TIMP-1 increased significantly as nephritis progressed in NZB/W F1 mice. At 48 weeks of age, the levels of mRNA for alpha 1(I), alpha 1(III), alpha 1(IV) collagen chains, laminin B1 and B2 chains, HSPG, MMP-1, -2, -3, and TIMP-1 were increased by 5.6- (P < 0.001), 3.6- (P < 0.01), 6.8- (P < 0.001), 5.2- (P < 0.001), 5.0- (P < 0.001), 6.0- (P < 0.001), 7.6- (P < 0.001), 4.2- (P < 0.01), 8.2- (P < 0.001), and 15.2-fold (P < 0.001), respectively, in the renal cortex of NZB/W F1 mice compared to NZW mice. Immunofluorescence microscopy showed that the accumulation of collagens I, III, and IV, laminin, and HSPG in the renal cortex of NZB/W F1 mice increased markedly with the progression of nephritis. At 20 weeks of age, NZB/W F1 and NZW mice were divided into two groups that received either FR139317 or its vehicle (saline) intraperitoneally, daily, for 28 weeks. The development of histological lesions, proteinuria, hypertension, accumulation of collagens I, III, and IV, laminin, and HSPG in the renal cortex of NZB/W F1 mice were suppressed by FR139317 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of a specific endothelin A receptor antagonist on murine lupus nephritis. 772 34

We compared two models of cardiac fibrosis in which collagen synthesis is controlled at different levels. Regulation is pretranslational in aldosterone-salt-induced hypertension in young rats and posttranslational in 24-month-old rats. However, little is known about the role of matrix metalloproteinases (MMP) in fibrosis development. Ventricular MMP activities were studied by zymography, and MMP-2 and MMP-1 mRNA levels were determined using slot-blot and ribonuclease protection assay, respectively. After 1 month of aldosterone-salt treatment, proMMP-2, MMP-2, and proMMP-1 collagenolytic activities and their gene expression were unchanged compared with sham-operated rats. After 2 months, total MMP-2 activity was increased by 40% with parallel stimulation of its gene expression. These changes were localized by in situ zymography within the media of coronary vessels. These results suggest that MMP play a prominent role in vascular remodeling during the first steps of hypertension. During aging, however, there were 40% and 45% decreases in MMP-2 and proMMP-1 activity, respectively, with a corresponding down-regulation of MMP-2 mRNA. These observations suggest that depression of the degradative pathway is partly responsible for age-associated fibrosis. Thus, MMP have differing involvements in the cardiac remodeling associated with hypertension or aging.
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PMID:Differential regulation of matrix metalloproteinases associated with aging and hypertension in the rat heart. 916 91

The degradation of collagen fibrils and elastic fibers in 21 cases of acute aortic dissection (AD) was ultrastructurally and immunohistochemically investigated; and the expression of the catabolic matrix metalloproteinases (MMPs)-1, -2, -3, and -9 and their inhibitors, the tissue inhibitors of matrix metalloproteinase (TIMPs)-1 and -2, was studied. The features of the entry site of the dissection (ES; 21 ascending aortas) were compared with those of fully remote sites (RS; 19 nondissected abdominal aortas) and the ascending aortas from 10 control cases. By electron microscopy, the medial layer at the ES and adjacent intact aortic wall demonstrated spirally thickened collagen fibrils with a typical banding pattern that were almost always colocalized with elastic lamellae, which often exhibited attenuation, fragmentation, or disruption. In addition, the basement membrane surrounding the smooth muscle cells (SMCs) comprising the media was frequently thinned or lost at the ES. These findings were rarely seen at the RS or in the aortas of controls. Immunohistochemically, the expression of MMP-1 was significantly in the cytoplasm of SMCs of both the intima and media at the ES and adjacent intact wall, and significant expression of MMP-2 and -9 was found in SMCs of the intima compared with the RS and controls. Significant expression of TIMP-1 and -2 was demonstrated in the cytoplasm of SMCs at the ES and adjacent intact wall compared with that at the RS and the control specimens. These findings suggest that the degradation of proteins associated with fibrosis and the occurrence of AD are not merely coincident, but rather that AD is induced by alterations of the extracellular matrix caused by changes of SMCs at a segment of the ascending aorta made vulnerable through hemodynamic stress, especially that caused by hypertension.
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PMID:Collagen and elastin degradation by matrix metalloproteinases and tissue inhibitors of matrix metalloproteinase in aortic dissection. 1123 Jul 15

Matrix metalloproteinase-1 (MMP-1), also called interstitial collagenase, may play an important role in the pathogenesis of atherosclerosis and atherosclerotic plaque rupture. We investigated the effects of fluvastatin on MMP-1 expression in human vascular endothelial cells (ECs). The addition of fluvastatin decreased the basal MMP-1 levels in the culture media of ECs in a time-dependent (0 to 48 hours) and dose-dependent (10(-)(8) to 10(-)(5) mol/L) manner. On the other hand, fluvastatin did not affect tissue inhibitor of metalloproteinase-1 levels. Collagenolytic activity in conditioned media of ECs was also dose-dependently reduced by fluvastatin. The effect of fluvastatin on MMP-1 expression was completely reversed in the presence of mevalonate or geranylgeranyl-pyrophosphate, but not in the presence of squalene. Inhibition of Rho by C3 exoenzyme also significantly decreased MMP-1 expression in ECs. Our findings revealed that fluvastatin decreases MMP-1 expression in human vascular ECs through inhibition of Rho.
Hypertension 2000 Sep
PMID:Fluvastatin inhibits matrix metalloproteinase-1 expression in human vascular endothelial cells. 1098 59

Angiotensin II (Ang II)-mediated stimulation of fibroblast growth and collagen type I synthesis is believed to be an important component of the cardiac remodeling process in hypertension and chronic ischemia. Ang II-mediated oxidative stress could be important in enhanced fibroblast growth and collagen formation. Accordingly, we postulated that the PPAR-gamma ligand, pioglitazone, which is known to modulate oxidative stress, would alter Ang II-induced formation of collagen type I in cardiac fibroblasts. Cardiac fibroblasts were treated with different concentrations (10(-8) to 10(-6) M) of Ang II for different times (6 hours, 12 hours, and 24 hours). Ang II increased the expression of collagen type I in a concentration- and time-dependent fashion (P<0.01 versus control). Ang II also decreased the expression and activity of matrix metalloproteinase (MMP)-1 (MMP-1, P<0.05 versus control). These effects of Ang II were attenuated by pretreatment of cells with pioglitazone (10 micromol/L). Ang II stimulated the intracellular generation of reactive oxygen species (ROS), and this effect was also attenuated by pioglitazone. Ang II treatment activated the redox-sensitive transcription factor NF-kappaB, and pioglitazone pretreatment blocked this effect of Ang II. Ang II also activated another transcription factor, AP-1, but this effect of Ang II was not modulated by pioglitazone. In other experiments, we observed that trolox, the water soluble analog of vitamin E, attenuated the effects of Ang II on the expression of collagen type I and MMP-1, in a manner similar to pioglitazone. Thus, pioglitazone attenuates Ang II-mediated collagen type I synthesis in cardiac fibroblasts. The effects of pioglitazone are mediated by the modulation of ROS release and redox-sensitive transcription factor NF-kappaB.
Hypertension 2004 Nov
PMID:Angiotensin II regulation of collagen type I expression in cardiac fibroblasts: modulation by PPAR-gamma ligand pioglitazone. 1538 78

Study of surgical specimens and direct observation by angioscopy has revealed that the varicose venous wall, the valvular annulus, and the valves themselves undergo profound changes. Morphologic investigations have shown dilation of the valve annulus, bulging valve leaflets, commissural dilation, leaflet stretching, and eventually complete destruction of the valves. The venous wall has been seen to undergo changes of thickening in some segments and thinning in others. Our investigations show that inflammation and subsequent remodeling of the venous valves and wall are the fundamental mechanisms underlying the observed lesions. Hemodynamic forces, such as blood pressure changes in the wall and sheer stress, as well as varying planes of laminar and turbulent flow, induce activation of leukocytes and endothelial cells. Integrins appear to act as intermediaries and expression of adhesion molecules has been observed. Breakdown of extracellular matrix of the media and adventitia through activation of matrix metalloproteases (MMP) has been observed. In particular, expressions of MMP-1, MMP-2, MMP-9, and tissue inhibitor of metalloproteinase have been studied. Telangiectasias, reticular veins, and true varicose veins appear to be a consequence of the changes induced by venous hypertension and sheer stress.
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PMID:Causes of telengiectasias, reticular veins, and varicose veins. 1579 45

Angiotensin II (Ang II)-mediated hypertension increases the risk for acute coronary syndrome, a consequence of atherosclerotic plaque rupture, which may be caused by matrix metalloproteinases (MMPs). Here, we show that human primary monocytes stimulated with tumor necrosis factor alpha (TNF-alpha) and granulocyte macrophage-colony stimulating factor (GM-CSF) release Ang II, which is an integral component of the signal transduction pathway that leads to MMP-1 production. An Ang II-mediated increase in MMP-1 synthesis occurred only in conjunction with cytokine stimulation. Moreover, Ang II mediated its effect through the Ang II type 2 (AT(2)) receptor, as demonstrated by enhancement of MMP-1 production by an AT(2) agonist, CGP-42112A, and inhibition of MMP-1 production by PD1233319, an AT(2) antagonist. Additionally, exogenous Ang II caused a significant enhancement in MMP-1 production by cytokine-stimulated monocytes, and the most effective enhancement occurrred when Ang II was added 6 h after stimulation. Furthermore, Ang II and the AT(2) agonist increased prostaglandin E(2) (PGE(2)), which in turn mediated the increase in MMP-1, as shown by the inhibition of MMP-1 by indomethacin or aspirin. In contrast, the AT(2) antagonist inhibited the PGE(2) production induced by TNF-alpha and GM-CSF. Ang II, through its interaction with the AT(2) receptor, has a central role in mediating the PGE(2)-dependent production of MMP-1 by monocytes stimulated with TNF-alpha and GM-CSF. These observations provide insight into the association between hypertension and acute coronary syndrome and a possible mechanism by which Ang-converting enzyme inhibitor and aspirin may reduce the risk for heart attacks.
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PMID:Angiotensin II increases human monocyte matrix metalloproteinase-1 through the AT2 receptor and prostaglandin E2: implications for atherosclerotic plaque rupture. 1581 99

The endothelial lectinlike, oxidatively (ox-) modified LDL receptor LOX-1 is a critical player in the pathogenesis of atherosclerosis and myocardial ischemia. Ox-LDL binding of LOX-1 results in the expression of various adhesion molecules, which attract monocytes to endothelial cells, an initial step in atherogenesis. We wished to examine the role of the ox-LDL/LOX-1 signaling pathway in fibroblasts, which naturally express low levels of LOX-1. Rat cardiac fibroblasts were transfected with either cytomegalovirus (CMV)-LOX-1wt (amino acids [aa] 1 to 273) or CMV-LOX-1(1-261) (an ox-LDL-binding negative mutant, aa 1 to 261) plasmid. Western blots showed that LOX-1 protein expression was increased significantly in cells transfected with CMV-LOX-1wt or CMV-LOX-1(1-261) plasmid (P<0.01 vs control). Fibroblasts transfected with CMV-LOX-1wt showed ox-LDL binding, whereas fibroblasts without transfection and those transfected with CMV-LOX-1(1-261) did not bind ox-LDL. Compared with untransfected cells, ox-LDL treatment (50 microg/mL, 24 hours) markedly induced the expression of the leukocyte adhesion molecules intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM)-1 as well as matrix metalloproteinase (MMP)-1 in cells transfected with CMV-LOX-1wt (P<0.05) but not in cells transfected with CMV-LOX-1(1-261). Concurrently, ox-LDL treatment enhanced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) (P<0.05 vs control) in CMV-LOX-1wt-transfected cells. These data suggest that in cardiac fibroblasts, ox-LDL binds to LOX-1 and activates p38 MAPK, followed by the expression of ICAM-1, VCAM-1, and MMP-1. Thus, fibroblasts transform into an endothelial phenotype on transfection with CMV-LOX-1wt and subsequent exposure to ox-LDL. This study provides a useful model system (plasmid-transfected fibroblasts) to study the molecular biology of LOX-1.
Hypertension 2005 Sep
PMID:Adhesion molecule expression in fibroblasts: alteration in fibroblast biology after transfection with LOX-1 plasmids. 1611 44

Collagen metabolism in the extracellular matrix (ECM) is related to the pathogenesis of cardiovascular stiffness and remodeling in hypertension. We evaluated the association between collagen metabolism markers and the newly developed parameter, brachial-ankle pulse wave velocity (baPWV), in older hypertensive patients with left ventricular hypertrophy (LVH). We performed echocardiography and baPWV measurement using a new device, form PWV/ABI (Colin Medical Technology, Komaki, Japan), and measured plasma levels of markers of collagen metabolism such as procollagen type I C-terminal propeptide (PICP: a marker of collagen synthesis), collagen type I pyridinoline cross-linked C-terminal telopeptide (ICTP: a marker of collagen type I degradation), matrix metalloproteinase-1 (MMP-1: a marker of collagen degradation) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in 46 hypertensive patients with LVH. BaPWV was correlated with the plasma level of PICP (r=0.33, p=0.03) and ICTP (r=0.29, p=0.05) and the total TIMP-1/MMP-1 ratio (an index of collagen turnover; r=0.30, p=0.04). BaPWV was negatively correlated with the E/A ratio of left ventricular inflow (r=-0.36, p<0.05), while baPWV was not correlated with left ventricular mass index (LVMI; r=-0.175, p=0.25) or deceleration time of the mitral E wave (DCT; r=0.15, p=0.31). The measures of hypertensive heart disease, such as the E/A ratio, DCT or LVMI were not correlated with any collagen markers in this study. In multiple regression analysis adjusted for confounding factors such as age, sex, pulse pressure, mean blood pressure, pulse rate, LVMI, E/A ratio and DCT, the positive correlation between baPWV and total TIMP-1/MMP-1 ratio remained significant (p<0.05). In conclusion, arterial stiffness in high-risk older hypertensive patients may involve ECM collagen metabolism.
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PMID:Collagen metabolism in extracellular matrix may be involved in arterial stiffness in older hypertensive patients with left ventricular hypertrophy. 1667 39

Arterial hypertension is associated with organ dysfunctions, but the mechanisms are uncertain. We hypothesized that enhanced proteolytic activity in the microcirculation of spontaneously hypertensive rats (SHRs) may be a pathophysiological mechanism causing cell membrane receptor cleavage and examine this for 2 different receptors. Immunohistochemistry of matrix-degrading metalloproteinases (matrix metalloproteinase [MMP]-9) protein shows enhanced levels in SHR microvessels, mast cells, and leukocytes compared with normotensive Wistar-Kyoto rats. In vivo microzymography shows cleavage by MMP-1 and -9 in SHRs that colocalizes with MMP-9 and is blocked by metal chelation. SHR plasma also has enhanced protease activity. We demonstrate with an antibody against the extracellular domain that the insulin receptor-alpha density is reduced in SHRs, in line with elevated blood glucose levels and glycohemoglobin. There is also cleavage of the binding domain of the leukocyte integrin receptor CD18 in line with previously reported reduced leukocyte adhesion. Blockade of MMPs with a broad-acting inhibitor (doxycycline, 5.4 mg/kg per day) reduces protease activity in plasma and microvessels; blocks the proteolytic cleavage of the insulin receptor, the reduced glucose transport; normalizes blood glucose levels and glycohemoglobin levels; and reduces blood pressure and enhanced microvascular oxidative stress of SHRs. The results suggest that elevated MMP activity leads to proteolytic cleavage of membrane receptors in the SHR, eg, cleavage of the insulin receptor-binding domain associated with insulin resistance.
Hypertension 2008 Aug
PMID:Proteinase activity and receptor cleavage: mechanism for insulin resistance in the spontaneously hypertensive rat. 1854 34


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