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

Vascular remodeling and rearrangement of the extracellular matrix formation are among the major adaptive mechanisms to chronic increase in blood pressure. In previous studies we have found that angiotensin II (Ang II) participates in the hypertension-associated aortic and renal vascular fibrosis by stimulating collagen type I formation. The purpose of the present study was to gain insight into the molecular events that lead from the Ang II receptor to collagen I gene activation. To this end, we used a novel strain of transgenic mice harboring the luciferase gene under the control of the collagen I-alpha(2) chain promoter [procolalpha(2)(I)]. Ang II produced an early (1 hour) 2- to 3-fold stimulation of procolalpha(2)(I) activity in freshly isolated aortas and renal cortical slices (P:<0. 01) followed by similar increase in procolalpha(2)(I) mRNA aortic levels. This effect of Ang II was inhibited by AT1-receptor antagonism (candesartan) and blockade of the MAPK/ERK cascade (PD98059); in contrast, inhibition of the P38 kinase pathway (SB202190) and blockade of the release of the transcription factor NFkappaB (PDTC) did not have any effect in the Ang II-induced activation of the collagen I gene. In addition, Ang II induced a rapid (5 minutes) increase of the MAPK/ERK activity that was accompanied by increased expression (3-fold) of the c-fos proto-oncogene. This increase of c-fos mRNA expression was blocked by PD98059; in addition, curcumin, a blocker of the transcriptional factor AP-1, canceled the effect of Ang II on the collagen I gene. Decorin, a scavenger of the active form of transforming growth factor-beta (TGF-beta), canceled the Ang II effect on collagen I gene, whereas inhibition of the MAPK/ERK pathway had no effect on the TGF-beta-induced activation of procolalpha(2)(I). These data indicate that the cellular events after AT1 receptor stimulation and leading to activation of collagen I gene expression require activation of both the MAPK/ERK and TGF-beta signaling pathways.
Hypertension 2000 Sep
PMID:Angiotensin II activates collagen I gene through a mechanism involving the MAP/ER kinase pathway. 1098 60

Aldosterone is implicated in cardiac hypertrophy and fibrosis. We tested the role of the mineralocorticoid receptor in a model of angiotensin II-induced cardiac injury. We administered spironolactone (SPIRO; 20 mg. kg(-1). d(-1)), valsartan (VAL; 10 mg. kg(-1). d(-1)), or vehicle to rats double transgenic for the human renin and angiotensinogen genes (dTGR). We investigated basic fibroblast growth factor (bFGF), platelet-derived growth factor, transforming growth factor-beta(1), and the transcription factors AP-1 and nuclear factor (NF)-kappaB. We used immunohistochemistry, electrophoretic mobility shift assays, and TaqMan RT-PCR. Untreated dTGR developed hypertension, cardiac hypertrophy, vasculopathy, and fibrosis with a 50% mortality rates at 7 weeks. SPIRO and VAL prevented death and reversed cardiac hypertrophy, while only VAL normalized blood pressure. Both drugs prevented vasculopathy. bFGF was markedly upregulated in dTGR, whereas platelet-derived growth factor-B and transforming growth factor-beta(1) were little changed. VAL and SPIRO suppressed this upregulation. Both AP-1 and NF-kappaB were activated in dTGR compared with controls. VAL and SPIRO reduced both transcription factors and reduced bFGF, collagen I, fibronectin, and laminin in the interstitium. These findings show that aldosterone promotes hypertrophy, cardiac remodeling, and fibrosis, independent of blood pressure. The effects involve AP-1, NF-kappaB, and bFGF. Mineralocorticoid receptor blockade downregulates these effectors and reduces angiotensin II-induced cardiac damage.
Hypertension 2001 Feb
PMID:Mineralocorticoid receptor affects AP-1 and nuclear factor-kappab activation in angiotensin II-induced cardiac injury. 1123 Mar 74

Autosomal dominant polycystic kidney disease (ADPKD) is a major, inherited disorder that is characterized by the growth of large, fluid-filled cysts from the tubules and collecting ducts of affected kidneys, and by a number of extrarenal manifestations including liver and pancreatic cysts, hypertension, heart valve defects, and cerebral and aortic aneurysms. Mutations in either of 2 different genes (PKD1 or PKD2) give rise to ADPKD. Most mutations identified in affected families appear to inactivate the PKD genes, and accumulating evidence suggests that a 2-hit mechanism, in which the normal PKD1 or PKD2 allele is also mutated, may be required for cyst growth. The protein products of the PKD genes (polycystin-1 and polycystin-2) are thought to function together as part of a multiprotein membrane-spanning complex involved in cell-cell or cell-matrix interactions. Polycystin-1 and polycystin-2 can initiate signal transduction, leading to the activation of a number of downstream effectors, including heterotrimeric G-proteins, protein kinase C, mitogen-activated protein kinases, beta-catenin, and the AP-1 transcription factor. In addition, polycystin-2 may function in mediating calcium flux. The pathogenesis of cyst formation is currently thought to involve increased cell proliferation, fluid accumulation, and basement membrane remodeling. It now appears that cyclic adenosine monophosphate (cAMP) metabolism is a central component of cyst formation, stimulating apical chloride secretion and driving the accumulation of cyst fluid. Recent evidence has shown that ADPKD cells also have an altered responsiveness to cyclic AMP. In contrast to normal kidney cells whose cell proliferation is inhibited by cyclic AMP, ADPKD cells are stimulated to proliferate. Thus, it is likely that an alteration in polycystin function transforms the normal cellular phenotype to one that responds to elevated cyclic AMP by an increased rate of cell proliferation and that the enlarging cyst expands by an increased rate of cyclic AMP-driven fluid secretion. Cyclic AMP and growth factors, including epidermal growth factor, have complementary effects to accelerate the enlargement of ADPKD cysts, and thereby to contribute to the progression of the disease. This knowledge should facilitate the discovery of inhibitors of signal transduction cascades that can be used in the treatment of ADPKD.
 ...
PMID:The genetics and physiology of polycystic kidney disease. 1124 74

Angiotensin (Ang) II has 2 major receptor isoforms, Ang type 1 (AT(1)) and Ang type (AT(2)). AT(1) transphosphorylates epidermal growth factor receptor (EGFR) to activate extracellular signal-regulated kinase (ERK). Although AT(2) was shown to inactivate ERK, the action of AT(2) on EGFR activation remains undefined. Using AT(2)-overexpressing vascular smooth muscle cells from AT(2) transgenic mice, we studied these undefined actions of AT(2). Maximal ERK activity induced by Ang II was increased 1.9- and 2.2-fold by AT(2) inhibition, which was abolished by orthovanadate but not okadaic acid or pertussis toxin. AT(2) inhibited AT(1)-mediated EGFR tyrosine phosphorylation by 63%. The activity of SHP-1 tyrosine phosphatase was significantly upregulated 1 minute after AT(2) stimulation and association of SHP-1 with EGFR was increased, whereas AT(2) failed to tyrosine phosphorylate SHP-1. Stable overexpression of SHP-1-dominant negative mutant completely abolished AT(2)-mediated inhibition of EGFR and ERK activation. AT(1)-mediated c-fos mRNA accumulation was attenuated by 48% by AT(2) stimulation. Induction of fibronectin gene containing an AP-1 responsive element in its 5'-flanking region was decreased by 37% after AT(2) stimulation, corresponding to the results of gel mobility assay with the AP-1 sequence of fibronectin as a probe. These findings suggested that AT(2) inhibits ERK activity by inducing SHP-1 activity, leading to decreases in AP-1 activity and AP-1-regulated gene expression, in which EGFR dephosphorylation plays an important role via association of SHP-1.
Hypertension 2001 Sep
PMID:Angiotensin II type 2 receptor inhibits epidermal growth factor receptor transactivation by increasing association of SHP-1 tyrosine phosphatase. 2370 57

Nonenzymatic glycation is increased in diabetes. The role of advanced glycation end products has been implicated in many of the complications of diabetes, whereas the effects of early-glycation Amadori-modified proteins on vascular cells alone are poorly defined. In the present study, we show that glycated serum albumin (GSA) induces a parallel activation of the redox-responsive transcription factors (nuclear factor kappaB) and AP-1 and increases activity of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), and p38 MAPK in vascular smooth muscle cells (VSMCs). GSA increased expression of early response genes, c-fos and c-jun, and inflammatory genes, monocyte chemoattractant peptide (MCP-1), and interleukin (IL)-6. These effects were comparable to bacterial lipopolysaccharide, tumor necrosis factor-alphaa, (TNF-alphaa), IL-1alphab, angiotensin II, epidermal growth factor, and the phorbol ester PMA. One of signaling pathways by which GSA activates VSMCs appears to be via nuclear factor kappaB activation, leading to induction of MCP-1 and IL-6 gene expression, comparable to the effects of lipopolysaccharide, TNF-alphaa, and IL-1alphab. Another signaling cascade by which GSA activates VSMCs is the ERK-->c-Fos-->AP-1 pathway, which may lead to stimulation of cell proliferation and migration. These effects are comparable to the effects of angiotensin II, epidermal growth factor, and PMA. Incubation of VSMCs with the antioxidant N-acetylcysteine suppressed GSA-elicited mRNA induction of MCP-1 and IL-6. Inhibition of p38 MAPK but not ERK caused attenuation of MCP-1 and IL-6 mRNA induction. Finally, GSA caused a significant stimulation of VSMC growth and migration. These findings suggest that GSA may play a role in diabetic atherogenesis by activating VSMCs, leading to induction of inflammatory mediators in the vessel wall, as well as proliferation and migration of VSMCs.
Hypertension 2002 Jan
PMID:Vascular smooth muscle cell activation by glycated albumin (Amadori adducts). 1179 73

The activator protein 1 (AP-1) transcriptional complex, containing Jun and Fos proteins, is involved in regulating many cellular processes such as proliferation and differentiation. However, little is known about a direct relationship between AP-1 activities and cardiomyocyte hypertrophy. To elucidate the roles of myocardial AP-1 activities, dominant negative mutant of c-Jun (DNJun) was overexpressed in cultured rat neonatal ventricular myocytes by adenovirus vector to abrogate endogenous AP-1 activation. Cardiomyocytes were treated with 100 nmol/L endothelin 1 (ET) and 10 micromol/L phenylephrine (PE) to induce myocardial cell hypertrophy. Both ET and PE significantly enhanced AP-1 DNA binding activities (3.4-fold by ET and 4.8-fold by PE at 3 hours, P<0.01). At 48 hours after stimulation, ET and PE significantly increased incorporation of (3)H-phenylalanine (1.4-fold by ET and 1.5-fold by PE, P<0.01), cell size (2.3-fold and 2.5-fold, P<0.01), and mRNA expression of atrial natriuretic peptide (ANP; 1.9-fold and 1.8-fold, P<0.01) and brain natriuretic peptide (BNP; 1.6-fold and 1.6-fold, P<0.01). Adenovirus carrying DNJun prevented the transcriptional activation of the AP-1 by ET and PE, using AP-1 reporter enzyme firefly luciferase assay. Moreover, DNJun prevented the increase in incorporation of (3)H-phenylalanine, cell size, and the mRNA expression of ANP and BNP by ET and PE. In conclusion, we provide the first evidence that DNJun inhibits cardiomyocyte hypertrophy through inhibition of AP-1 transcriptional activity.
Hypertension 2002 Jan
PMID:Dominant negative mutant of c-Jun inhibits cardiomyocyte hypertrophy induced by endothelin 1 and phenylephrine. 1179 83

Dihydropyridines can inhibit gene expression in-vitro and may have a protective vascular effect independent of blood pressure reduction. We tested the hypothesis that lacidipine prevents induction of inducible NO synthase (iNOS), influences leukocyte adhesion and infiltration, inhibits nuclear factor (NF)-kappaB transcription factor activity, and ameliorates end-organ damage in a transgenic rat model of angiotensin (Ang) II--dependent organ sclerosis. We treated rats transgenic for human renin and angiotensinogen (dTGR) from week 4 to 7 with lacidipine (0.3 or 3 mg/kg by gavage). Blood pressure was measured by tail cuff. Organ damage was assessed by histology and immunohistochemistry. Adhesion molecules and cytokines were analyzed by immunohistochemistry. Transcription factors were analyzed by mobility shift assays. Untreated dTGR developed moderate hypertension, cardiac hypertrophy, and severe renal damage with albuminuria. Lacidipine decreased blood pressure slightly at the low dose and substantially at the higher dose. However, both treatments reduced albuminuria and plasma creatinine to the same degree (P<0.05). Intercellular adhesion molecule-1 (ICAM-1) was markedly reduced by lacidipine as well as renal neutrophil and monocyte infiltration. Lacidipine reduced mitogen-activated protein (MAP) kinase phosphorylation and iNOS expression in both cortex and medulla. NF-kappaB and AP-1 were activated in dTGR but reduced by lacidipine. Lacidipine ameliorates Ang II-induced end-organ damage independent of blood pressure lowering, perhaps by inhibiting the MAP kinase pathway and NF-kappaB activation.
Hypertension 2002 Feb
PMID:Lacidipine inhibits adhesion molecule and oxidase expression independent of blood pressure reduction in angiotensin-induced vascular injury. 1188 31

In the past decade, substantial progress has been made concerning our knowledge of bioactive components in plant foods and their links to health. Human diets of plant origin contain many hundreds of compounds which cannot be considered as nutrients, but appear to play a role in the maintenance of health. These substances are called nutraceuticals. In some cases where the disease process is at least partially understood, elements of protection can be related to a single compound or structurally related group of compounds in the diet. Bioactive components of food which are of special interest include the following groups: polyphenols, phytoestrogens, phytosterols, phytates and polyunsaturated fatty acids. Most of them are featured by antioxidant properties. In the first part of this review, we indicate the main groups of bioactive compounds giving a description of their localisation, chemical properties and biological actions. Recently, it was shown, however, that the bioavailability of potential antioxidants from plant foods is generally too low to have any substantial direct effect on reactive oxygen species. As a result of that it is postulated that dietary compounds, even in very low concentrations, may have a far greater impact than previously appreciated on the regulation of gene expression. The second part of this paper concerns the action of the literally most important bioactive substances on the molecular mechanisms of the control of genes which in turn affect cellular metabolism. A few current studies on the action of selected nutraceuticals on the activity of transcription factors such as AP-1, NF-kappaB, SREBPs, PPARs as final targets in the signal transduction cascade and gene regulation are included. A detailed analysis of numerous factors of dietary origin with their targets is far beyond the scope of this paper. However, continuing research on the effects of nutraceuticals on gene expression should provide insight into the mechanisms of prevention of diseases such as obesity, diabetes, atherosclerosis, hypertension and cancer by dietary manipulations.
 ...
PMID:Bioactive substances of plant origin in food--impact on genomics. 1253 56

Biochemical and genetic evidence support the involvement of leukocyte-type 12/15-lipoxygenase enzyme and its products in the atherogenic process. We recently showed that products of the 12/15-lipoxygenase pathway play an important role in mediating hypertrophy, matrix protein production, and inflammatory gene expression in vascular smooth muscle cells (VSMC) through activation of mitogen activated protein kinases and key transcription factors. The current study is aimed at establishing the in vivo role of 12/15-lipoxygenase in VSMC by comparing growth factor-induced responses in VSMC derived from 12/15-lipoxygenase knockout mice versus genetic control wild-type mice. In the lipoxygenase knockout cells, 12/15-lipoxygenase protein was not expressed, and levels of its product, 12(S)-hydroxyeicosatetraenoic acid, were reduced (51% of wild type). Knockout cells exhibited significantly lower rates of growth factor-induced migration, fibronectin production, and incorporation of 3H-thymidine and 3H-leucine (54%, 55%, 61%, and 57% of wild type, respectively). Growth factor-induced superoxide production and p38 mitogen-activated protein kinase activation were also reduced in knockout cells. Serum-stimulated AP-1 transcription factor activation was markedly reduced (50% of wild type), whereas cAMP response element binding protein activation was abrogated in knockout cells. Furthermore, growth factor-induced mRNA expression of immediate early genes and fibronectin were also greatly reduced. These results suggest that the modulation of specific signaling pathways and growth-responsive genes may be responsible for the altered growth factor responses in the lipoxygenase knockout cells. They also demonstrate the important in vivo role of vascular 12/15-lipoxygenase in VSMC growth, migration, and matrix responses associated with hypertension, atherosclerosis, and restenosis.
Hypertension 2003 Jun
PMID:Reduced growth factor responses in vascular smooth muscle cells derived from 12/15-lipoxygenase-deficient mice. 1270 89

Prostaglandin D(2) (PGD(2)) and its metabolites bind to the intracellular PPARs to regulate vasoactive substances involved in vascular remodeling through regulation of mRNAs transcription as well as through receptor-mediated mechanisms. PGD(2) decreases inducible NO, PAI-1, endothelin, and VCAM expression through inhibition to NF kappa B, STAT, or AP-1 transcription factors, which are regulated by cytokines/immune system. Moreover, transfer of L-PGDS (PGD(2) synthase) into the intracellular space of EC or SMC increases intracellular PGD(2), thereby decreasing these substances. PGD(2) attenuates in vivo organ injury mediated by cytokines and the immune system. The pretreatment with PGD(2) attenuates the liver damage and hemodynamic collapse following LPS. Dahl salt-sensitive rats, with decreased PGD(2) in the outer medulla of the kidney, are prone to hypertensive kidney injury. Serum L-PGDS level is increased in renal dysfunction through a decrease in glomerular filtration. L-PGDS in urine may be derived from a failure of tubular reabsorption or from in situ synthesis. Urinary L-PGDS excretion markedly increases in the early stage of kidney injury, and urinary L-PGDS is a useful predictor of the forthcoming renal injury. Indeed, urinary L-PGDS precedes clinically overt proteinuria or other parameters indicating renal dysfunction in hypertension, primary renal diseases, and diabetes in humans. PGD(2)/L-PGDS system is a Cinderella of vascular biology.
 ...
PMID:[PGD(2)/L-PGDS system in hypertension and renal injury]. 1469 55


<< Previous 1 2 3 4 5 6 7 8 Next >>