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)

Endothelin-1 stimulates collagen synthesis and is increased in hypertension, but its effect on collagen degradation remains unknown. The current study tested the hypothesis that elevated endothelin-1 levels are associated with decreased collagenase activity, markers of collagen degradation, and arterial compliance in hypertensive patients. Normotensive (n = 10) and hypertensive (n = 13) patients who were not on any antihypertensive medication were recruited, and small and large artery elasticity index, systemic vascular resistance, pulse pressure, and blood pressure were determined using blood pressure waveform analysis. Large artery elasticity index and collagen degradation products were decreased whereas endothelin-1, systemic vascular resistance, and pulse pressure were elevated in hypertensive patients. Plasma endothelin-1 was negatively correlated with a cross-linked C-terminal telopeptide of collagen type I, a collagen degradation marker (r = -0.43; p = 0.04), collagenase matrix metalloproteinase-1 (r = -0.48; p = 0.02), and large artery elasticity (r = -0.45; p = 0.03) and positively correlated with pulse pressure (r = 0.68; p = 0.0005). These results suggest that endothelin-1 contributes to decreased arterial compliance in hypertension via inhibition of collagen degradation.
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PMID:Elevated endothelin-1 levels are associated with decreased arterial elasticity in hypertensive patients. 1689 70

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

Angiotensin II exerts its central nervous system effects primarily via its receptors AT1 and AT2, and it participates in the pathogenesis of ischemia via AT1. The selective AT1 receptor blocker (ARB) is used in the hypertension treatment, and it exerts a variety of pleiotropic effects, including antioxidative, antiapoptotic, and anti-inflammatory effects. In this study, we investigated the therapeutic effect of the ARB telmisartan in experimental intracerebral hemorrhage (ICH) in normotensive rats. ICH was induced via the collagenase infusion or autologous blood injection. Either telmisartan at 30 mg/kg/dose or phosphate-buffered saline was orally administered 2 h after ICH induction. We evaluated hemorrhage volume, brain water content, and functional recovery, and we performed the histological analysis for terminal deoxynucleotidyl transferase dUTP nick-end labeling, leukocyte infiltration, and microglia activation. A variety of intracellular signals, in terms of oxidative stress, apoptotic molecules, and inflammatory mediators, were also measured. Telmisartan reduced hemorrhage volume, brain edema, and inflammatory or apoptotic cells in the perihematomal area. Telmisartan was noted to induce the expression of endothelial nitric-oxide synthase and peroxisome proliferator-activated receptor gamma and decrease oxidative stress, apoptotic signal, tumor necrosis factor-alpha, and cyclooxygenase-2 expression. The telmisartan-treated rats exhibited less pronounced neurological deficits and recovered better. Thus, telmisartan seems to offer neural protection, including antiapoptosis, anti-inflammatory, and antioxidant benefits in the intracerebral hemorrhage rat model.
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PMID:Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. 1753 8

The extracellular matrix is vital for maintaining tissue integrity, and the matrix metalloproteinases/tissue inhibitors of metalloproteinases (MMPs/TIMPs) system is involved in the regulation of extracellular matrix metabolism. Extracellular matrix turnover plays an important role in the change of large arterial mechanical properties in hypertension. However, the association of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 (MMP-9/TIMP-1) system and arterial stiffness is not straightforward and existing data are rather limited. Our objective is to explore the impact of the MMP-9/TIMP-1 system on large arterial stiffness in patients with essential hypertension. An automatic pulse wave velocity (PWV) measuring system was used to examine carotid-femoral PWV (CFPWV) and carotid-radial PWV (CRPWV) as the parameters reflecting central elastic large arterial and peripheral muscular medium-sized arterial elasticity, respectively; and serum MMP-9 and TIMP-1 levels, along with a number of other established biomarkers, were measured by enzyme-linked immunosorbent assay (ELISA) in 202 essential hypertensive patients and 54 age and gender-matched control subjects. Compared with the control subjects, hypertensive patients exhibited higher levels of MMP-9 (p=0.001) and TIMP-1 (p=0.002). Spearman's correlation analysis showed that serum levels of MMP-9 (p=0.014) and TIMP-1 (p=0.005) were significantly and positively correlated with CFPWV in hypertensive patients. A stepwise multiple regressive analysis demonstrated that age, systolic blood pressure, heart rate and TIMP-1 were independent predictors of CFPWV in patients with essential hypertension (adjusted r2=0.458). In conclusion, our results imply that the MMP-9/TIMP-1 system may play an important role in the determination of arterial function, and these findings may have implications for the involvement of MMP-9/TIMP-1 system in the pathophysiology of cardiovascular disease.
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PMID:Impact of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system on large arterial stiffness in patients with essential hypertension. 1804 28

Aim of the study was to investigate interrelationship between serum markers of myocardial fibrosis: matrix metalloproteinase -1 (MMP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and parameters of echocardiography in patients with arterial hypertension (AH) and paroxysmal form of atrial fibrillation (n=39). We revealed positive correlation of levels of TIMP-1 with thickness of interventricular septum in diastole (r=0,47, p=0,02), peak velocity of late filling of the right ventricle (r=0,46, p=0,01), and negative relation between MMP-1 levels and degree of mitral and tricuspid regurgitation (r=0,43, p=0,005 and r=0,38, p=0,04, respectively). In the group of patients with increased left ventricular myocardial mass index (LVMMI) TIMP-1 level was significantly higher than in patients with normal LVMMI (p < 0,05). In the group combining patients with concentric and eccentric LV hypertrophy TIMP-1 level was significantly higher than in the group combining patients with LV concentric remodeling and normal geometry (p < 0,05). No correlations were revealed between MMP-1 and TIMP-1 levels and parameters of diastolic dysfunction. In patients with AH increase of serum concentrations of TIMP-1 was associated with increased thickness of interventricular septum, increase of LVMMI, and with prognostically unfavorable types of LV remodeling.
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PMID:[Metalloproteinase activity of the blood in patients with arterial hypertension with paroxysmal form of atrial fibrillation]. 1826 Sep 72

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

Hypertension induces dysfunctional matrix remodeling that results in the development of myocardial fibrosis. Myocardial fibrosis adversely affects compliance, electrical activity and cardiac function in patients with hypertensive heart disease. Matrix metalloproteinases (MMPs) are a class of enzymes that regulate the remodeling of the matrix in response to pressure overload. Several studies have shown that the MMP-1/TIMP (tissue inhibitor of matrix metalloproteinase) ratio is decreased in hypertensive heart disease. However, the exact role that MMP-1 has in modulating the fibrotic response to hypertension is largely unknown. We hypothesized that cardiac expression of MMP-1 in mice would protect against the development of dysfunctional matrix remodeling during pressure overload. To investigate this, a suprarenal aortic banding model was utilized. Banded and unbanded MMP-1 transgenic mice were compared with appropriately matched wild-type mice. The banded mice were examined at 2 and 5 weeks after banding. MMP-1 attenuated the development of cardiac fibrosis, prevented left ventricular dilation and preserved cardiac function in mice that were exposed to pressure overload. Thus, MMP-1 protected the heart from the dysfunctional remodeling that occurs in response to chronic hypertension. In conclusion, these results suggest that strategies aimed at improving the MMP-1/TIMP balance in the myocardium may help to prevent the onset and progression of hypertensive heart disease.
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PMID:Transgenic expression of matrix metalloproteinase-1 inhibits myocardial fibrosis and prevents the transition to heart failure in a pressure overload mouse model. 1863 85

The left ventricle (LV) remodels with age and in response to pressure overload. While aging and pressure overload are superimposed in the clinical context, the structural and functional consequences of the individual processes are not well-understood. Accordingly, the objective of this study was to compare the effects of both early and late chronic hypertension on extracellular matrix (ECM) remodeling. The following groups of Dahl rats were studied: 1) young salt-resistant (control, n=6); 2) young salt-sensitive (early phase of chronic hypertension, n=6); 3) middle-aged salt-resistant (aging, n=5); and 4) middle-aged salt-sensitive (late phase of chronic hypertension, n=6). We measured LV mass (LVM) and body weight (BW) and immunoblotted a panel of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and ECM proteins. Total collagen increased, several MMPs decreased, and TIMP-1 increased in the early phase of hypertension, consistent with fibrosis. Active MMP-8 decreased from 8,010+/-81 U in young salt-resistant to 5,260+/-313 U in young salt-sensitive (p<0.05) rats. During the late phase, chronic hypertension decreased total collagen levels and increased MMP-8 and MMP-14 (all p<0.05). Based on good-fit modeling analysis, MMP-14 (45 kDa) correlated positively with changes in LVM/BW during the early phase. In conclusion, this is the first study to evaluate MMP levels during both early and late chronic phases of hypertension. Our results highlight that ECM remodeling in response to pressure overload is a dynamic process involving excessive ECM accumulation and degradation.
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PMID:Effects of early and late chronic pressure overload on extracellular matrix remodeling. 1871 51

Atrial fibrillation (AF) is the most common rhythm disturbance in medical practice and represents a very expensive health problem. AF can be managed with the prevention of thromboembolism and either a rate control of rhythm strategy. As both strategies have important limitations, probably a preventative strategy in patients at risk of developing arrhythmia can be a more attractive option. The renin-angiotensin system (RAS) seems to be involved in the genesis of arrhythmia by the following two mechanisms: 1. the induction of atrial fibrosis and structural remodelling by mitogen-activated protein kinase (MAPK) expression and reduction of collagenase activity; 2. the induction of electrical remodelling by shortening of the atrial effective refractory period (AERP) and of the action potential duration. For these reasons it has been hypothesized that angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin-II receptor blockers (ARBs) may play a role in preventing AF recurrence. The aim of the present review was to analyse evidence supporting the usefulness of RAS inhibition in patients with AF in order to focus on which specific subset of patients it would most favour. After reviewing the literature, we conclude that, although many studies and meta-analysis have supported the advantage of RAS block in preventing AF recurrence, it is premature to recommend the use of ACE-Is and ARBs specifically for the prevention of AF. However we believe that as these drugs are safe and manageable, they should be considered the drugs of choice in patients with AF and coexisting clinical conditions such as hypertension, coronary disease, heart failure and diabetes mellitus.
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PMID:The role of the renin-angiotensin system in atrial fibrillation and the therapeutic effects of ACE-Is and ARBS. 1878 41

Elastolysis, collagenolysis and gelatinolysis are essential in the pathogenesis of tobacco smoke-induced emphysema; however, these activities have been scantily studied in emphysema secondary to woodsmoke. The aim of this study was to analyze elastolysis, collagenolysis and gelatinolysis, MMP-1, MMP-2, and MMP-9 expression, and apoptosis in guinea pigs exposed to smoke produced by 60 g/day of pine wood, 5 days/week, from 1 to 7 months. Histological analysis after 4 to 7 months in smoke exposed guinea pigs showed alveolar mononuclear phagocyte and lymphocytic peribronchiolar inflammation, epithelial and smooth muscle hyperplasia, and pulmonary arterial hypertension. Mild to moderate emphysematous lesions were observed in woodsmoke-exposed animals at 4 to 7 months by increase of mean linear intercepts. A higher percentage of whole blood carboxyhemoglobin (COHb) and elastolytic activity in bronchoalveolar lavage macrophages and lung tissue homogenates was observed at all times. Collagenolysis was increased after 4 to 7 months in woodsmoke-exposed animals, although collagen concentration did not change. Zymography revealed increase in lysis bands of the active MMP-2 and MMP-9 at 4 and 7 months in bronchoalveolar lavage fluid and lung tissue homogenate. Positive immunostaining for MMP-1 and MMP-9 was observed in epithelial cells and macrophages in wood exposed animals at 4 to 7 months. Real-time PCR showed MMP-2 and MMP-9 expression at 3 to 7 months in exposed animals. Furthermore, apoptosis was increased at all times in bronchoalveolar lavage macrophages and lung tissue from exposed animals. Results support a role of metalloproteinases and apoptosis in emphysema secondary to woodsmoke exposure.
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PMID:Increase of matrix metalloproteinases in woodsmoke-induced lung emphysema in guinea pigs. 1883 20


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