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)

In this study, we focused on the effect of hypertension on the transcription factors nuclear factor kappaB (NFkappaB) and ets in the mechanisms of abdominal aortic aneurysm (AAA), and we investigated how hypertension affects the progression of AAA. AAA was produced by elastase perfusion in hypertensive rats and normotensive rats. The size of AAA rapidly increased in hypertensive rats as compared with normotensive rats. Western blot analysis demonstrated that the expression of matrix metalloproteinase (MMP)-2, -3 , -9, and -12, as well as intercellular adhesion molecule, was increased in hypertensive AAA rats, accompanied by upregulation of NFkappaB and ets. Moreover, in situ zymography showed that the activity of MMPs was increased in the aorta of a hypertensive AAA model as compared with that in a normotensive AAA model. Interestingly, transfection of chimeric decoy oligodeoxynucleotide (ODN) resulted in significant inhibition of aortic dilatation both in normotensive and hypertensive rats at 4 weeks after transfection. Destruction of elastic fibers was also significantly inhibited by transfection of chimeric decoy ODN in both hypertensive rats and normotensive rats. The expression of MMP-2, -3, -9, and -12, as well as intercellular adhesion molecule, was significantly attenuated by the chimeric decoy ODN, accompanied by inhibition of the migration of macrophages. Also, the effect of chimeric decoy ODN was confirmed in an organ culture. The present study demonstrated that hypertension accelerated the progression of experimental AAA through upregulation of NFkappaB and ets. Inhibition of NFkappaB and ets could be a novel therapeutic strategy to treat AAA in hypertensive patients.
Hypertension 2006 Oct
PMID:Hypertension accelerated experimental abdominal aortic aneurysm through upregulation of nuclear factor kappaB and Ets. 1694 Feb 14

The present study examined the pathogenesis of interstitial inflammation and fibrosis in antihypertensively treated rats with two-kidney, one-clip hypertension. Hypertensive rats were randomized into four groups: no treatment and moderate, intermediate, and intensified lowering of blood pressure with increasing doses of a vasopeptidase inhibitor for 6 wk. The vasopeptidase inhibitor dose dependently lowered blood pressure. The tubulointerstitial damage was accompanied by a diffuse infiltration of mononuclear cells and circumscript mononuclear inflammatory cell cluster formation consisting mainly of T cells and to a lesser degree of macrophages and B cells. Real-time PCR analyses showed a dose-dependent induction of MCP-1 and the Th1-type chemokines IP10 and Mig as well as their receptor CXCR3 and the Th1 cytokine IFN-gamma. In situ hybridization and laser microdissection revealed a strong expression of these Th1-associated transcripts in the clusters and, in the case of MCP-1, also diffusely in the interstitium. The inflammation was accompanied by the appearance of myofibroblasts and synthesis of the fibrogenic factor plasminogen activator inhibitor-1 as well as the collagenase matrix metalloproteinase-2, leading to collagen I upregulation and interstitial scarring. No inflammation or fibrosis was found in normotensive rats treated with the vasopeptidase inhibitor. The renal injury in the clipped kidney is accompanied by compartment-specific chemokine expression and cell cluster formation of Th1 specificity associated with upregulation of fibrogenic proteins and matrix metalloproteinases. These findings suggest that the Th1 chemokines IP10 and Mig as well as their receptor CXCR3 are potential targets for therapeutic interventions in ischemic nephropathy.
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PMID:Antihypertensive therapy induces compartment-specific chemokine expression and a Th1 immune response in the clipped kidney of Goldblatt hypertensive rats. 1706 48

Obesity is a common disorder and related diseases such as diabetes, atherosclerosis, hypertension, cardiovascular disease and cancer are a major cause of mortality and morbidity in Western-type societies. Development of obesity is associated with extensive modifications in adipose tissue involving adipogenesis, angiogenesis and extracellular matrix proteolysis. The fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems cooperate in these processes. A nutritionally induced obesity model in transgenic mice has been used extensively to study the role of the fibrinolytic and MMP systems in the development of obesity. These studies support a role of both systems in adipogenesis and obesity; the role of specific members of these families, however, remains to be determined.
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PMID:Role of the fibrinolytic and matrix metalloproteinase systems in development of adipose tissue. 1717 99

Sympathetic nerve activity increases in the heart during cardiac failure. Here, we hypothesized that beta1 integrins play a protective role in chronic beta-adrenergic receptor-stimulated cardiac myocyte apoptosis and heart failure. L-isoproterenol (iso; 400 microg/kg per hour) was infused in a group of wild-type (WT) and beta1 integrin heterozygous knockout (hKO) mice. Left ventricular structural and functional remodeling was studied at 7 and 28 days of iso-infusion. Western blot analysis demonstrated reduced beta1 integrin levels in the myocardium of hKO-sham. Iso-infusion increased heart weight:body weight ratios in both groups. However, the increase was significantly higher in WT-iso. M-mode echocardiography indicated increased left ventricular end-diastolic diameter, percentage of fractional shortening, and ejection fraction in the WT-iso group. The percentage of fractional shortening and ejection fraction were significantly lower in hKO-iso versus hKO-sham and WT-iso. Peak left ventricular developed pressure and left ventricular end-diastolic pressure measured using Langendorff-perfusion analyses were significantly higher in the WT-iso group (P<0.05 versus WT-sham and hKO-Iso). The number of TUNEL-positive myocytes was significantly higher in hKO-iso hearts 7 and 28 days after iso-infusion. The increase in myocyte cross-sectional area and fibrosis was higher in the WT-iso group. Matrix metalloproteinase-9 protein levels were significantly higher in WT-iso, whereas matrix metalloproteinase-2 levels were increased in hKO-iso hearts. Iso-infusion increased phosphorylation of c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 in both groups. The increase in c-Jun N-terminal kinase phosphorylation was significantly higher in hKO-iso (P<0.001 versus WT-iso). Thus, beta1 integrins play a crucial role in beta-adrenergic receptor-stimulated myocardial remodeling with effects on cardiac myocyte hypertrophy, apoptosis, and left ventricular function.
Hypertension 2007 Apr
PMID:Beta1 integrins modulate beta-adrenergic receptor-stimulated cardiac myocyte apoptosis and myocardial remodeling. 1729 73

Whether morning blood pressure surge influences the molecular mechanisms of plaque progression toward instability is not known. Recently, we have demonstrated enhanced activity of the ubiquitin-proteasome system in human plaques and evidenced that it is associated with inflammatory-induced plaque rupture. We evaluated the inflammatory infiltration and ubiquitin-proteasome activity in asymptomatic carotid plaques of hypertensive patients with different patterns of morning blood pressure surge. Plaques were obtained from 32 hypertensive patients without morning blood pressure surge and 28 with morning blood pressure surge enlisted to undergo carotid endarterectomy for extracranial high-grade (>70%) internal carotid artery stenosis. Plaques were analyzed for macrophages, T-lymphocytes, human leukocyte antigen-DR+cells, ubiquitin-proteasome activity, nuclear factor-kappaB, inhibitor kB-beta, tumor necrosis factor-alpha, nitrotyrosine, matrix metalloproteinase-9, and collagen content (immunohistochemistry and ELISA). Compared with plaques obtained from hypertensive patients without morning blood pressure surge, plaques from with morning blood pressure surge had more macrophages, T-lymphocytes, human leukocyte antigen-DR+cells (P<0.001), ubiquitin-proteasome activity, tumor necrosis factor-alpha, nuclear factor-kB (P<0.001), nitrotyrosine, and matrix metalloproteinase-9 (P<0.01), along with a lesser collagen content and IkB-beta levels (P<0.001). Enhanced ubiquitin-proteasome activity in atherosclerotic lesions of patients with morning blood pressure surge is associated with inflammatory-dependent unstable plaque phenotype. These data suggest a potential interplay between morning blood pressure surge and ubiquitin-proteasome activity in atherosclerosis pathophysiology.
Hypertension 2007 Apr
PMID:Morning blood pressure surge as a destabilizing factor of atherosclerotic plaque: role of ubiquitin-proteasome activity. 1732 33

Progressive cardiac remodeling is characterized by subsequent chamber hypertrophy, enlargement, and pump dysfunction. It is also associated with increased cardiac fibrosis and matrix turnover. Interestingly, peroxisome proliferator-activated receptor (PPAR) alpha activators reduce cardiac hypertrophy, inflammation, and fibrosis. Little is known about the role of fenofibrates in mediating PPARalpha-independent effects in response to chronic pressure overload (PO). Wild-type and PPARalpha-deficient mice were subjected to chronic PO caused by ascending aortic constriction to test the role of fenofibrates in chronic, progressive cardiac remodeling by a PPARalpha-independent mechanism. Mice were randomized to regular chow or chow-containing fenofibrate (100 mg/kg of body weight per day) for 1 week before and 8 weeks after ascending aortic constriction. In the presence of PPARalpha, wild-type chronic PO mice, treated with fenofibrate, had improved cardiac remodeling. However, PO PPARalpha-deficient mice treated with fenofibrate had increased mortality, significantly adverse left ventricular end diastolic (3.4+/-0.1 versus 4.2+/-0.1 mm) and end systolic (1.5+/-0.2 versus 2.5+/-0.2 mm) dimensions, and fractional shortening (57+/-3% versus 40+/-3%). Fenofibrate also increased myocardial hypertrophy, cardiac fibrosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2 in PO PPARalpha-deficient mice. Fenofibrate inhibited matrix metalloproteinase activity in vitro and aldosterone-induced increases in extracellular signal-regulated kinase phosphorylation. Thus, fenofibrate improved cardiac remodeling in chronic PO mice. However, in PPARalpha-deficient mice, this chronic PO was exacerbated and associated with increased myocardial fibrosis and altered matrix remodeling. In the absence of PPARalpha, fenofibrates exerts deleterious, pleiotropic myocardial actions. This is an important observation, because PPARalpha agonists are considered possible inhibitory regulators of cardiac remodeling in the remodeled heart.
Hypertension 2007 May
PMID:Peroxisome proliferator-activated receptor alpha-independent actions of fenofibrate exacerbates left ventricular dilation and fibrosis in chronic pressure overload. 1735 9

Hypertension is associated with vascular remodeling characterized by rearrangement of extracellular matrix proteins. To evaluate how matrix metalloproteinase (MMP)-9 contributes to the progression of hypertensive vascular disease in vivo, wild-type (wt) or MMP-9(-/-) mice were treated with angiotensin II (Ang II; 1 microg/kg per minute, by minipump) plus a 5% NaCl diet during 10 days. Baseline blood pressure was equivalent in wt and knockout mice, but Ang II treatment increased systolic blood pressure to a greater extent (P<0.05) in MMP-9(-/-) mice (94+/-6 to 134+/-6 mm Hg; P<0.001) than in wt animals (93+/-4 to 114+/-6 mm Hg; P<0.01). In wt mice, Ang II treatment increased the carotid artery pressure-diameter relationship significantly, and maximal diameter reached 981+/-19 microm (P<0.01 versus sham; 891+/-10 microm). In contrast, in MMP-9(-/-) mice, carotid artery compliance was actually reduced after Ang II (P<0.05), and maximal diameter only reached 878+/-13 microm. Ang II treatment induced MMP-2 and increased carotid media thickness equally in both phenotypes. However, MMP-9 induction and in situ gelatinase activity were only enhanced in Ang II-treated wt mice, and vessels from these mice also produced more collagen I breakdown products than their MMP-9(-/-) counterparts (P<0.05). Inversely, staining for collagen IV was particularly enhanced in vessels from MMP-9(-/-) mice treated with Ang II. These results demonstrate the following: (1) the onset of Ang II-induced hypertension is accompanied by increased MMP-9 activity in conductance vessels; (2) absence of MMP-9 activity results in vessel stiffness and increased pulse pressure; and (3) MMP-9 activation is associated with a beneficial role early on in hypertension by preserving vessel compliance and alleviating blood pressure increase.
Hypertension 2007 Jul
PMID:Role of matrix metalloproteinases in early hypertensive vascular remodeling. 1751 50

1. The present study was designed to examine the role of amlodipine in preventing and reversing monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats. 2. Rats were injected with MCT (40 mg/kg, s.c.) and randomly given either 6 mg/kg per day of amlodipine in drinking water or placebo for 3 weeks. Any animals treated with MCT that survived for 3 weeks were given either amlodipine or placebo for the next 3 weeks. 3. Blood pressure was not different between the groups. Amlodipine immediately following MCT markedly inhibited PAH with severe pulmonary vascular remodelling. The survival rate at 3 weeks after treatment was increased significantly in the amlodipine group compared with the placebo group (77%vs 43%; P < 0.01). The placebo group showed markedly diminished expression of endothelial nitric oxide synthase (eNOS) protein and mRNA levels, increased numbers of proliferating cell nuclear antigen-positive cells, enhanced mRNA expression of matrix metalloproteinase-2 and pro-inflammatory cytokines in the lung tissue and upregulation of P-selectin on the endothelium of the pulmonary arteries, whereas these effects were suppressed in the amlodipine-treated group. Furthermore, late treatment with amlodipine did not palliate PAH or improve survival. 4. Amlodipine inhibited the development of PAH and improved survival in rats independent of its effect on lowering blood pressure. These effects were associated with marked inhibition of the downregulation of eNOS and improvement of pulmonary vascular endothelial activation, as well as anti-inflammatory, antiproliferative and antifibrotic effects in the lung tissue. However, amlodipine failed to reverse established PAH. This study may provide an insight into therapeutic strategy of amlodipine in PAH.
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PMID:Amlodipine prevents monocrotaline-induced pulmonary arterial hypertension and prolongs survival in rats independent of blood pressure lowering. 1758 Dec 14

Hypertension and cardiac remodeling are associated with myocardial fibrosis, left ventricular (LV) hypertrophy, and diastolic heart failure. Fenofibrate suppresses aldosterone-mediated increases in myocyte matrix metalloproteinase activity and extracellular signal-regulated kinase phosphorylation. It is unknown whether the peroxisome proliferator-activated receptor-alpha agonist, fenofibrate, improves cardiac remodeling in a model of aldosterone-induced hypertension and LV hypertrophy. Twelve-week-old uninephrectomized FVB mice received 1% NaCl drinking water. Miniosmotic pumps delivered saline or aldosterone for 4 weeks. Mice were either untreated (n=14) or treated with fenofibrate 100 mg/kg per day (n=12) for 1 week before and 4 weeks after surgery. Aldosterone increased systolic blood pressure in untreated mice versus saline-untreated mice (134+/-3 versus 91+/-3 mm Hg; P<0.01). This was unaffected by fenofibrate (131+/-3 mm Hg). Aldosterone increased LV end-diastolic and end-systolic dimensions, which were significantly attenuated by fenofibrate (3.8+/-0.1 versus 3.5+/-0.1 mm, and 1.5+/-0.1 versus 1.15+/-0.1 mm, respectively). Fenofibrate also decreased aldosterone-induced LV hypertrophy (LV weight/body weight, 4.1+/-0.2 versus 4.6+/-0.1 mg/g) and improved percent LV fractional shortening (67+/-7% versus 60+/-2%). Additionally, fenofibrate ameliorated the increased matrix metalloproteinase-2/tissue inhibitors of metalloproteinase-2 ratio and fibrosis seen in aldosterone-untreated hearts (P<0.05 for both). Furthermore, in aldosterone-untreated hearts, fenofibrate decreased transforming growth factor-beta, collagen type III (P<0.05 for both), and collagen type I (P<0.01) protein expression. Conversely fenofibrate increased peroxisome proliferator-activated receptor-alpha, peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression, and acetyl coenzyme A carboxylase phosphorylation (P<0.05 for all) in aldosterone-infused hearts; uncoupling protein-3 and medium-chain acyl coenzyme A dehydrogenase protein expression decreased with fenofibrate (P<0.05 and P<0.01, respectively, versus aldosterone-infused), suggesting that improved myocardial remodeling is independent of fatty acid oxidation. Thus, fenofibrate improved aldosterone-induced LV hypertrophy independently of an effect on blood pressure with decreased fibrosis and altered extracellular matrix.
Hypertension 2007 Sep
PMID:Effects of fenofibrate on cardiac remodeling in aldosterone-induced hypertension. 1760 58

Obesity is a major risk factor for the development of hypertension. Recent studies have suggested that leptin, a 167-amino acid peptide hormone produced by white adipose tissue, is related to the pathogenesis of obesity-related hypertension. However, the signaling mechanisms underlying the effects of leptin remain to be extensively examined. In this study, we found that leptin induced extracellular signal-regulated kinase phosphorylation and endothelin-1 expression in rat aortic smooth muscle cells. Both PD98059 and U0126, inhibitors of the upstream activator of mitogen-activated protein kinase kinase, inhibited augmentation of endothelin-1 expression stimulated with leptin. Leptin induced significant tyrosine phosphorylation of epidermal growth factor receptor, which was significantly attenuated by two inhibitors, an epidermal growth factor receptor tyrosine kinase inhibitor, AG1478, and a broad-spectrum matrix metalloproteinase inhibitor, GM6001. This indicates that the pathway of epidermal growth factor receptor transactivation induced by leptin is dependent on proteolytically released epidermal growth factor receptor ligands. Pretreatment of cells with AG1478 significantly reduced the degree of phosphorylation of extracellular signal-regulated kinase and endothelin-1 expression. Our results reveal that epidermal growth factor receptor transactivation is involved in the leptin signaling pathway in vascular smooth muscle cells, which may be related to the increased risk of hypertension and other cardiovascular diseases in obese subjects.
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PMID:Leptin stimulates endothelin-1 expression via extracellular signal-regulated kinase by epidermal growth factor receptor transactivation in rat aortic smooth muscle cells. 1767 88


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