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)

Elevations in plasma angiotensin II (AngII) are associated with evidence of vascular hyperpermeability expressed as efflux of plasma macromolecules into the perivascular and interstitial space. This exudative response is followed by a series of fibrogenic events that lead to a perivascular fibrosis of involved vessels. Mediators of hyperpermeability and fibrogenesis are unknown. In dogs receiving intravenous AngII, hemodynamic factors (i.e., arterial hypertension or coronary venoconstriction) were discounted as being responsible for the rise in cardiac lymph-to-plasma protein ratio. Accordingly, we investigated the relationship between AngII-induced coronary hyperpermeability and the release of prostaglandin E2 (PGE2) and activation of the basement membrane degrading matrix metalloproteinase, gelatinase/type IV collagenase. In dogs, cardiac lymph was monitored over the course of a 90-minute intravenous infusion of either AngII (0.2 to 0.3 micrograms/kg/min; n = 8) or saline solution (n = 6). Lymph was examined at 30-minute intervals for the following: total protein (Lowry's method), albumin (sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)), plasma fibronectin (SDS-PAGE and enzyme-linked immunosorbent assay); PGE2 (radioimmunoassay) and gelatinase/type IV collagenase (zymography). In comparison with baseline we found a consistent rise in lymph flow (p = 0.02), total protein (p = 0.02), albumin, fibronectin, PGE2 (p = 0.03), and gelatinase/type IV collagenase (p = 0.019), which began after 30 minutes of AngII infusion. Similar trends were not observed in dogs receiving saline solution alone. We therefore conclude that AngII-induced coronary vascular hyperpermeability is associated with an early release of PGE2 and gelatinase.
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PMID:Coronary vascular hyperpermeability and angiotensin II. 766 80

Mortality of patients with severe congestive heart failure (CHF) is still high despite combined treatment with angiotensin-converting enzyme (ACE) inhibitors, diuretics, and digitalis. Further therapeutic regimens are needed which include reversal of adverse myocardial remodeling and subsequent ventricular dysfunction. One third of all patients with CHF have diastolic left ventricular (LV) dysfunction with preserved systolic function. In these patients myocardial collagen matrix is the major determinant of myocardial stiffness and therefore diastolic function. Cardiac fibroblasts, expressing mRNA for types I and III collagens which are the major fibrillar proteins of the myocardial collagen network and for matrix metalloproteinase (MMP) 1 which is the key enzyme for interstitial collagen degradation, are controlled by the renin-angiotensin-aldosterone (RAAS) system irrespective of hemodynamics and cardiac myocyte growth. In the rat with primary or secondary hyperaldosteronism, myocardial fibrosis occurs in the pressure overloaded, hypertrophied left and in the normotensive, nonhypertrophic right ventricle. In contrast, no fibrosis is found in either ventricle of rats with infrarenal aortic banding, when the RAAS is not activated, despite comparable systemic hypertension and LV hypertrophy. In cultured cardiac fibroblasts, either effector hormone of the RAAS, angiotensin (Ang) II and aldosterone (Aldo) stimulate collagen synthesis measured by 3H-proline incorporation under serum-free conditions. Aldo is able to stimulate collagen synthesis normalized per total protein synthesis in a dose-dependent manner and at concentrations (10(-9) M) which are comparable to stimulated states in vivo (e.g., CHF). While Aldo does not affect collagen degradation AngII significantly inhibits, MMP 1 activity that would lead to further accumulation of collagen in the myocardium. Specific AngII type I or Aldo receptor antagonists are able to abolish the AngII or Aldo-mediated increase in collagen synthesis, respectively. In vivo in rats with primary or secondary hyperaldosteronism, the Aldo antagonist spironolactone has been shown to prevent myocardial fibrosis in both ventricles irrespective of the development of LV hypertrophy and hypertension. Thus, in vivo and in vitro evidence could be provided that the mineralocorticoid. Aldo, plays a pivotal role in promoting myocardial fibrosis and can be antagonized by its competitive receptor blocker, spironolactone. This may be of particular clinical relevance in treating patients with CHF where the RAAS is activated leading to myocardial fibrosis with subsequent deterioration of myocardial function. Clinical trials are needed to confirm these experimental data. If the ongoing RALES mortality study will prove that survival and/or morbidity of patients with CHF are improved by combined ACE inhibitor/spironolactone treatment a renaissance of anti-aldosterone therapy in patients with CHF would occur.
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PMID:[Spironolactone: renaissance of anti-aldosterone therapy in heart failure?]. 919 51

-To characterize remodeling of elastic arteries with aging and to investigate its potential mechanisms, matrix metalloproteinase-2 (MMP-2), intracellular adhesive molecule-1 (ICAM-1), transforming growth factor-beta (TGF-beta), and fibronectin protein levels were measured in the aortas of young adult (6 months) and aged (30 months) Fischer 344XBN rats. At 30 versus 6 months, the thickness of the intima was 5-fold greater and contained marked increases in TGF-beta and ICAM-1, and fibronectin expression was enhanced throughout the aortic wall. Total MMP-2 protein (Western blot) of 30-month-old rats was increased 8-fold over that of 6-month-old rats (0.166+/-0.032 versus 0.020+/-0.006; P<0.01), and staining and activity were regionally localized to the intima, often near breaks in the internal elastic membrane and lamellae. Early passage, explanted smooth muscle cells (SMC) from aged aorta secreted more MMP-2 than those from young aorta; while basal MMP-2 production did not differ with age, after stimulation with cytokines (interleukin-1, tumor necrosis factor-alpha, or TGF-beta, 10 ng/mL each for 24 hours), MMP-2 production in SMC from 30-month-old rats increased to levels greater than those in 6-month-old rats. Thus, enhanced expression of TGF-beta, MMP-2, and ICAM-1 in the thickened vascular intima of aged rats may in part be produced by exaggerated SMC responses to cytokines and may have potential roles in intimal remodeling with aging.
Hypertension 1999 Jan
PMID:Increased expression of matrix metalloproteinase-2 in the thickened intima of aged rats. 993 Oct 91

As clinical oncologists, our ultimate goal in treating patients with cancer is to be able to cure their disease with a combination of treatment modalities directed at the primary tumor (surgery or radiation), and potential metastases (chemotherapy). The validity of this multimodality approach to treating cancer was initially demonstrated with the successful treatment and cure of highly chemosensitive childhood cancers, such as Wilms' tumor, and these cures were only realized when adjuvant chemotherapy was included with local control measures. We attribute our treatment successes in childhood cancers to the use of cytotoxic chemotherapy, and we attribute our inability to cure many adults with more common forms of solid tumors to the ineffectiveness of chemotherapy in these diseases. Curing disease is not the goal of most pharmacological interventions in nonmalignant diseases. With the exception of antimicrobial and anticancer chemotherapy, most of the common classes of drugs are administered with the intent of controlling the disease or the symptoms caused by disease. We administer antihypertensive agents to control blood pressure, but the underlying cause of the hypertension is not cured by this therapy. If the hypertension recurs after antihypertensive therapy is stopped, we would conclude that the therapy was successful at controlling the disease. However, if a patient's tumor relapses after completing anticancer chemotherapy, the anticancer therapy would be considered to be unsuccessful. By setting lofty goals for our therapy, we increase the probability that the treatment will not meet our own and our patient's expectations. Schipper et al. [J Clin Oncol 1995;13:801-805] proposed that we abandon the "killing paradigm," which dictates that the treatment of cancer is directed toward eradication of all cancer cells, and that we adopt a "regulatory model" of cancer. This model views cancer as a maladaptive, constantly evolving process in which cancer cells differ only slightly from normal cells as a result of a few critical genetic changes that lead to dysregulation of growth. The treatment approach under this new paradigm is debulking of tumor burden with standard multimodality therapy followed by control of residual disease by "reregulation" of the remaining cancer cells. Controlling growth and spread of this residual disease would be accomplished with non-cytotoxic agents which target pathways that are responsible for the dysregulation in cancer cells. We are now on the verge of having the capacity to test this new paradigm of cancer. Advances in our understanding of the pathogenesis of many common forms of cancer at a molecular level have led to a revolution in anticancer drug development. A number of new agents that target a variety of critical molecular targets, such as the farnesyl transferase inhibitors that block ras oncogene activation, the matrix metalloproteinase inhibitors that block the enzymes involved in tissue invasion and metastasis [Editor's note: please see "New Drugs on the Horizon, page 271], and the angiogenesis inhibitors that block new vessel formation in growing tumors, are now being clinically tested. These new classes of anticancer drugs are aimed at regulating or controlling cancers rather than killing them. The potential utility of targeting the critical molecular lesion in tumor cells is illustrated by the efficacy of all-trans-retinoic acid in acute promyelocytic leukemia (APL). Although the capacity of all-trans-retinoic acid to induce complete remissions by inducing terminal differentiation of leukemic blasts was discovered empirically, the subsequent demonstration that the pathognomonic 15:17 translocation that is present in up to 90% of cases of APL results in the production of a dysfunctional retinoid receptor appears to explain the specificity and high level of activity of retinoid therapy in this disease. This is the first example of a cancer that can be treated by specifically targeting therapy to a pathogenetic molecular lesion. Retinoids are now being used in combination with standard chemotherapy for the treatment of APL, an example of the successful application of combining a molecularly targeted agent with conventional cytotoxic chemotherapy. The development and use of molecularly targeted agents for the treatment of cancer may require us to view cancer in a new light and to adjust our goals and expectations of its treatment as well as the endpoints of our clinical trials. However, pharmacologically controlling cancer may result in an equally acceptable outcome for our patients if it leads to what Schipper et al. termed a "functional cure."
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PMID:The Goal of Cancer Treatment. 1038 18

Altered degradation of extracellular matrix (ECM) underlies vascular remodeling, a hallmark in the pathogenesis of cardiovascular diseases including hypertension and aneurysmal dilatation. Although alcohol is recognized as a risk factor for certain cardiovascular disease states, its role in vascular remodeling has not been completely explored. We studied the effect of chronic alcohol consumption on upregulation of the enzymatic activity of matrix metalloproteinase-2 (MMP-2) as a possible pathway for large vessel remodeling. For this purpose, female rats were placed on one of three diets: a modified Lieber-DeCarli liquid diet containing 35% ethanol-derived calories, a pair-fed liquid diet with ethanol replaced by isocaloric maltose-dextrin, or a standard rat pellet. Weekly blood alcohol concentration averaged 117+/-7.9 mg/dl for the alcohol-fed rats. At 2, 4, and 72 weeks, aortas were removed and processed for measuring MMPs activity by gelatin zymography. Aortic extracts from rats on long-term (72 weeks), but not the short-term (2 and 4 weeks), alcohol diets showed increased MMP-2 activity. Furthermore, histochemical analysis of the aortas showed distinct disruption of the elastic fibers only in the 72 weeks alcohol-fed rats, compared to the control animals. These observations demonstrate that long-term alcohol consumption up-regulates MMP-2 activity, which is coincident with the alteration of aortic ECM composition through the degradation of vascular elastin components.
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PMID:Long-term alcohol consumption increases matrix metalloproteinase-2 activity in rat aorta. 1050 58

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

Elevated blood pressure imposes increased mechanical stress on the vascular wall, and mechanical strain is a mitogenic stimulus for vascular smooth muscle (VSM) cells. The role of mechanical forces in regulating the production of noncellular material by VSM cells for VSM cells of human origin remains undefined. We thus investigated the effects of chronic cyclical mechanical strain on extracellular matrix (ECM) protein production by cultured human VSM cells. To simulate a blood pressure of 120/80 mm Hg, human VSM cells were repetitively stretched and relaxed by 10% to 16% of their original length with the Flexercell apparatus. Fibronectin and collagen protein concentrations, matrix metalloproteinase (MMP) activity, and transforming growth factor-beta(1) (TGF-beta(1)) mRNA expression by human VSM cells were measured in response to mechanical strain. Exposing human VSM cells to 5 days of chronic cyclical mechanical strain increased fibronectin (+48%, P:<0.01) and collagen (+50%, P:<0.001) concentrations when compared with cells grown in static conditions. Mechanical strain also increased MMP-2 activity, the predominant matrix-degrading isoform (+11%, P:<0.05) in human VSM cells, thus strain-induced ECM accumulation was not due to inhibition of ECM protein degradation. Strain also increased TGF-beta(1) mRNA expression and the production of a soluble factor that increased ECM protein production. Moreover, a TGF-beta-blocking antibody inhibited the effect of strain-conditioned media on matrix production by human VSM cells. These results suggest that chronic cyclical mechanical strain can directly modulate the fibrogenic activity of human VSM cells by inducing ECM protein synthesis and MMP activity. This occurs, at least in part, through mechanical strain-induced TGF-beta(1) production, a mechanism that could explain the increased vascular ECM deposition in hypertension.
Hypertension 2000 Sep
PMID:Mechanical strain-induced extracellular matrix production by human vascular smooth muscle cells: role of TGF-beta(1). 1098 58

Estrogen replacement therapy significantly decreases the incidence of cardiovascular disease in postmenopausal women. In aging, there is an increase in vascular stiffness along with a decrease in matrix metalloproteinase (MMP) activity. Our hypothesis was that estrogen replacement would increase MMPs and therefore reduce the vascular stiffness that is associated with aging. Female Sprague-Dawley rats were implanted with a placebo or 17ss-estradiol-containing pellet (0.5 mg/pellet, 60-day release) at 10 months of age (n=6, each). Six young rats (3 months old) were also studied. After a 2-month exposure to the pellet, mesenteric arteries were studied on a pressurized arteriograph system. Distensibility and wall thickness were measured in response to stepwise increases in intraluminal pressure in Ca(2+)-free physiological saline solution buffer with papaverine (10(-4) mol/L). In response to increasing pressure, aged placebo rats exhibited a significant decrease in distensibility compared with young rats (P<0.05) that was accompanied by an increase in wall thickness (P<0.05). Conversely, estrogen replacement increased distensibility and decreased wall thickness in aged rats (old estrogen-replaced versus old placebo, P<0.05). Zymography data indicated that MMP-2 activity decreased in aging but was increased by estrogen replacement. In summary, estrogen replacement in aging female rats reduces age-associated vascular remodeling.
Hypertension 2000 Dec
PMID:Estrogen replacement reduces age-associated remodeling in rat mesenteric arteries. 1111 9

Presence or absence of three distinct bovine seminal heparin-binding proteins (21-31 kDa) recognized in sperm extracts by a monoclonal antibody, M1, is a diagnostic indicator of fertility differences among bulls producing normal semen. We recently identified a 31 kDa fertility-associated antigenin bovine seminal fluid as a unique DNase I-like protein. We now report purification and identification of a 24 kDa seminal heparin-binding protein (HBP-24) recognized by M1. N-terminal microsequence analysis of HBP-24 purified from seminal fluid yielded 20 amino acid residues that displayed 90% identity to the N-terminus of a bovine metalloproteinase inhibitor identified as tissue inhibitor of metalloproteinases-2 (TIMP-2). A single immunoreactive band migrating at 24 kDa was detected in Western blots of cauda epididymal sperm extracts following incubation with purified seminal heparin-binding proteins and subsequent washing in vitro, indicating TIMP-2 bound to sperm membranes. Expression of TIMP-2 mRNA was detected by RT-PCR in bovine bulbourethral gland, prostate, and seminal vesicles. Mobility of the 24 kDa heparin-binding protein increased under nonreducing SDS-PAGE to approximately 21 kDa, characteristic of the reported molecular mass of TIMP-2. To our knowledge, this is the first report of TIMP-2 binding to spermatozoa and of TIMP-2 mRNA expression in bovine accessory sex glands. These results corroborate previous reports regarding the site of production of heparin-binding proteins that are related to bull fertility, and suggest that TIMP-2 influences fertility of bulls, either through inhibition of metalloprotease activity in semen or via undefined activities independent of matrix metalloproteinase (MMP) inhibition.
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PMID:Identification of a heparin-binding protein in bovine seminal fluid as tissue inhibitor of metalloproteinases-2. 1117 Feb 75

P:eroxisome proliferator-activated receptor-gamma (PPARgamma) is a novel nuclear receptor, which enhances insulin-mediated glucose uptake. Ligands to PPARgamma are currently used as therapy for type II diabetes. Using Western blot analysis, RNase protection assay, and immunostaining, we identified the presence of PPARgamma message and protein in cultured primary rat mesangial cells. Electrophoretic mobility of a labeled PPARgamma response element (PPRE) was retarded in the presence of mesangial cell nuclear extract, suggesting that PPARgamma is functional in these cells. The addition of unlabeled PPRE efficiently competed away the PPARgamma-PPRE protein complex, confirming specificity of binding of the PPARgamma to the PPRE. PPARgamma ligands rosiglitazone (1 to 10 micromol/L) and troglitazone (1 to 10 micromol/L) inhibited platelet-derived growth factor-induced DNA synthesis, measured as bromodeoxyuridine incorporation (P<0.01). This inhibition was dose dependent. When administered in antidiabetic doses to streptozotocin-induced diabetic rats, troglitazone substantially normalized albumin excretion at 3 months (from 687.1 to 137.6 microgram urinary albumin/mg creatinine, P:<0.05) but did not affect hyperglycemia or blood pressure in this model. This treatment also decreased glomerular plasminogen activator inhibitor-1 (PAI-1) expression. These data suggest that PPARgamma activation may directly attenuate diabetic glomerular disease, possibly by inhibiting mesangial growth, which occurs early in the process of diabetic nephropathy, or by inhibiting PAI-1 expression. PAI-1 inhibits the activation of plasmin and matrix metalloproteinase, which degrade extracellular matrix in the glomerulus. Excess glomerular PAI-1 allows the accumulation of extracellular matrix, leading to glomerulosclerosis. These results have therapeutic implications for diabetic nephropathy as well as for proliferative mesangial diseases of the kidney.
Hypertension 2001 Feb
PMID:Expression and function of peroxisome proliferator-activated receptor-gamma in mesangial cells. 1123 Mar 63


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