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)

Reactive oxygen species (ROS) have been shown to mediate the effects of several growth factors and vasoactive peptides, such as epidermal growth factor, platelet-derived growth factor, and angiotensin II (AII). Endothelin-1 (ET-1) is a vasoactive peptide which also exhibits mitogenic activity in vascular smooth muscle cells (VSMCs), and is believed to contribute to the pathogenesis of vascular abnormalities such as atherosclerosis, hypertension, and restenosis after angioplasty. However, a possible role for ROS generation in mediating the ET-1 response on extracellular signal-regulated kinases 1 and 2 (ERK1/2), protein kinase B (PKB), and protein tyrosine kinase 2 (Pyk2), key components of the growth-promoting and proliferative signaling pathways, has not been examined in detail. Our aim was to investigate the involvement of ROS in ET-1-mediated activation of ERK1/2, PKB, and Pyk2 in A-10 VSMCs. ET-1 stimulated ERK1/2, PKB, and Pyk2 phosphorylation in a dose- and time-dependent manner. Pretreatment of A-10 VSMCs with diphenyleneiodonium (DPI), an inhibitor of reduced nicotinamide adenine dinucleotide phosphate oxidase, attenuated ET-1-enhanced ERK1/2, PKB, and Pyk2 phosphorylation. In addition, in parallel with an inhibitory effect on the above signaling components, DPI also blocked ET-1-induced protein synthesis. ET-1 was also found to increase ROS production, which was suppressed by DPI treatment. N-Acetylcysteine, a ROS scavenger, exhibited a response similar to that of DPI and inhibited ET-1-stimulated ERK1/2, PKB, and Pyk2 phosphorylation. These results demonstrate that ROS are critical mediators of ET-1-induced signaling events linked to growth-promoting proliferative and hypertrophic pathways in VSMCs.
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PMID:Reactive oxygen species mediate Endothelin-1-induced activation of ERK1/2, PKB, and Pyk2 signaling, as well as protein synthesis, in vascular smooth muscle cells. 1520 92

Recent advances in the treatment of colorectal cancer (CRC) include the incorporation of new drugs to treat a disease where only one drug was known to be active. Oxaliplatin and irinotecan have been incorporated into 5-fluorouracil (5-FU)-based regimens where they have increased response rates and survival. Targeted therapies against the epidermal growth factor pathway and the vascular endothelial growth factor (VEGF) pathway are also on the forefront of oncology research, and are beginning to play a role in the treatment of CRC. Current research efforts are trying to optimize the integration of targeted therapies into chemotherapy regimens such as IFL (irinotecan/bolus 5-FU/leucovorin [LV]), FOLFIRI (irinotecan/infusional 5-FU/LV), and FOLFOX (oxaliplatin/infusional 5-FU/LV). In this article, the incorporation of the monoclonal antibody bevacizumab into the IFL regimen will be reviewed in detail. Bevacizumab targets VEGF-A, an important angiogenesis signaling factor commonly expressed in metastatic CRC. The addition of bevacizumab to the IFL regimen significantly increased response rates, median time to progression, and overall survival in patients receiving first-line treatment for CRC, thus leading the Food and Drug Administration to approve bevacizumab for the treatment of CRC in combination with 5-FU-based regimens. Bevacizumab treatment is associated with an increased rate of hypertension. In addition, there may be slight (1%-2%) but relevant increased risks related to gastrointestinal perforations and cardiovascular events. A modest increased risk of wound healing complications was observed in patients who underwent surgery while still receiving, or shortly after receiving, bevacizumab. Bevacizumab plus 5-FU is also a highly active first-line regimen. The role of bevacizumab with other first-line combination regimens, as well as its activity in the second-line setting, is now being determined by ongoing clinical trials.
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PMID:Integrating the anti-VEGF-A humanized monoclonal antibody bevacizumab with chemotherapy in advanced colorectal cancer. 1547 81

Endothelin represents a necessary intermediate of angiotensin II-induced resistance artery remodeling in hypertension. Recent data suggest that epidermal growth factor receptors are rapidly transactivated by angiotensin II stimulation to mediate its growth-promoting effects. Because endothelin also transactivates epidermal growth factor receptors in vitro, we studied the contribution of epidermal growth factor receptor transactivation in the in vivo trophic actions of the upstream effector angiotensin II and its downstream mediator endothelin in rat mesenteric arteries. Twenty-six-hour infusion of angiotensin II (400 ng/kg per min) or endothelin (5 pmol/kg per min) via osmotic pumps significantly enhanced vascular protein synthesis. With angiotensin II, treatment with the inhibitor of epidermal growth factor receptor transactivation (AG1478, 0.5 mg/kg) produced a significant attenuation (P < 0.05) of protein synthesis. In contrast, AG1478 did not abrogate the elevation of protein synthesis induced by endothelin. In conclusion, angiotensin II-induced epidermal growth factor receptor transactivation seems to be involved in the recruitment of endothelin in the cascade leading to vascular protein synthesis, rather than in the effect of endothelin on small artery remodeling.
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PMID:EGF receptor transactivation in angiotensin II and endothelin control of vascular protein synthesis in vivo. 1583 79

An apparent low prevalence of cancer in hypertensive patients receiving angiotensin converting enzyme inhibitors is reported; however, the molecular mechanisms have not been elucidated. Angiotensin-II (Ang-II) is well known to be associated with hypertension, as a main peptide of the renin-angiotensin system, and its detailed molecular mechanisms have recently been elucidated. For instance, Ang-II directly activates the mitogenic signal transduction pathway through the angiotensin-II type-1 (AT1) receptor in smooth muscle cells and cardiac myocytes. Ang-II receptor blockers (ARBs), a class of antihypertensive agent, suppress signal transduction pathways mediated by growth factors such as epidermal growth factor (EGF), through the AT1 receptor. Our studies demonstrated that an ARB had the potential for antiproliferative effects and inhibition of angiogenesis in prostate cancer cells. The AT1 receptor is categorized in the guanosine phosphate binding protein-coupled receptors (GPCRs), which are viewed as critical regulators of the interactions between epithelial and stromal cells. Hence, we consider that in overcoming prostate cancer, it is very important to inhibit GPCR signaling in cancer cells by ARBs. It is unclear how prostate cancer growth changes from being hormone dependent to independent, and no effective therapy has therefore been developed. Our clinical data revealed that ARB administration decreased prostate specific antigen (PSA) and improved performance status in patients with hormone-refractory prostate cancer. This review provides an insight into the key role of Ang-II and the possibility of ARBs for molecular targeting of mitogenesis and angiogenesis in prostate cancer.
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PMID:Antiproliferative efficacy of angiotensin II receptor blockers in prostate cancer. 1610 80

In synthetic phenotype vascular smooth muscle cells (VSMC), activation of epidermal growth factor (EGF) receptor (EGFR) induces a sustained increase in intermediate conductance K(Ca) (int-K(Ca); K(Ca)3.1) channels that is essential for proliferation. However, a comparable mechanism has not been identified in native contractile phenotype VSMC, which express large conductance K(Ca) (maxi-K(Ca); K(Ca)1.1) channels, not int-K(Ca) channels. Using patch clamp of freshly isolated contractile VSMC from rat basilar artery, we found that EGF (100 ng ml(-1)) caused hyperpolarization (7.9 +/- 3.9 mV) due to activation of iberiotoxin-sensitive, maxi-K(Ca) channels. The EGFR ligands EGF (100 ng ml(-1)), transforming growth factor alpha (0.4 ng ml(-1)) and heparin-binding EGF (100 ng ml(-1)) all caused a 20% increase in maxi-K(Ca) channel current that was blocked by AG-1478 or by knock-down of EGFR expression using cisterna magna infusion of antisense oligodeoxynucleotide (AS-ODN). In controls, EGFR knock-down, and EGFR gain-of-expression (angiotensin II hypertension), the increase in maxi-K(Ca) current correlated with the abundance of EGFR protein expressed. The EGFR-mediated increase in maxi-K(Ca) channel activity was blocked by inhibiting cAMP-dependent protein kinase (cAK) using KT-5720 or Rp-cAMP, or by inhibiting adenylate cyclase type 5 (AC-5) using 2',5'-dideoxyadenosine or knock-down of AC-5 expression by intracisternal AS-ODN. Direct infusion of EGF into cisterna magna caused up-regulation of proliferating cell nuclear antigen (PCNA) in VSMC that was prevented by coinfusion of iberiotoxin or of AG-1478. Our data, which are consistent with the hypothesis that hyperpolarization is critical for a proliferative response, are the first to implicate AC-5 and maxi-K(Ca) channels in gene activation related to EGFR signalling in native contractile VSMC.
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PMID:Adenylate cyclase 5 and KCa1.1 channel are required for EGFR up-regulation of PCNA in native contractile rat basilar artery smooth muscle. 1629 43

Visceral fat accumulation has been shown to play crucial roles in the development of cardiovascular disease as well as the development of obesity-related disorders such as diabetes mellitus, hyperlipidemia and hypertension and the so-called metabolic syndrome. Given these clinical findings, adipocytes functions have been intensively investigated in the past 10 years, and have been revealed to act as endocrine cells that have been termed adipocytokines, which secrete various bioactive substances. Among adipocytokines, tumor necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin binding epidermal growth factor-like growth factor are produced in adipocytes as well as other organs, and may contribute to the development of vascular diseases. Visfatin has been identified as a visceral-fat-specific protein that might be involved in the development of obesity-related diseases, such as diabetes mellitus and cardiovascular disease. On the contrary to these adipocytokines, adiponectin, an adipose-tissue-specific, collagen-like protein, has been noted as an important antiatherogenic and antidiabetic protein, or as an anti-inflammatory protein. The functions of adipocytokine secretion might be regulated dynamically by nutritional state. Visceral fat accumulation causes dysregulation of adipocyte functions, including oversecretion of tumor necrosis factor-alpha, plasminogen activator inhibitor type 1 and heparin binding epidermal growth factor-like growth and hyposecretion of adiponectin, which results in the development of a variety of metabolic and circulatory diseases. In this review, the importance of adipocytokines, especially focusing on adiponectin is discussed with respect to cardiovascular diseases.
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PMID:The metabolic syndrome and adipocytokines. 1667 47

Coronary artery disease (CAD) is the leading cause of death worldwide and is commonly caused by a constellation of risk factors called the metabolic syndrome. We characterized a family with autosomal dominant early CAD, features of the metabolic syndrome (hyperlipidemia, hypertension, and diabetes), and osteoporosis. These traits showed genetic linkage to a short segment of chromosome 12p, in which we identified a missense mutation in LRP6, which encodes a co-receptor in the Wnt signaling pathway. The mutation, which substitutes cysteine for arginine at a highly conserved residue of an epidermal growth factor-like domain, impairs Wnt signaling in vitro. These results link a single gene defect in Wnt signaling to CAD and multiple cardiovascular risk factors.
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PMID:LRP6 mutation in a family with early coronary disease and metabolic risk factors. 1733 14

Angiogenesis inhibitors that target the epidermal growth factor (EGF) receptor (EGFR) and vascular endothelial growth factor (VEGF) constitute an important addition to the therapeutic armamentarium for the treatment of patients with metastatic disease. However, because the same growth factors are expressed in the kidneys, these treatment molecules have renal side effects. EGFR is expressed mainly in tubules (mainly distal and collecting segments) and mesangial and parietal epithelial cells. EGF is involved in maintaining tubular integrity and is a potent mitogen for cultured mesangial cells. Few cases of acute renal failure have been reported related to EGFR inhibitors. VEGF and VEGF receptors are still highly expressed in the kidney. VEGF is expressed in podocytes in the glomerulus, and VEGF receptors are present on endothelial, mesangial, and peritubular capillary cells. Signaling between endothelial cells and podocytes is essential for the proper development and maintenance of the filtration function of the kidney glomerulus. The most common renal class effects of VEGF antagonists are both manageable; hypertension and proteinuria commonly regressive on drug withdrawal. There was a dose-dependent increase in risk of proteinuria and hypertension in patients with cancer who received targeted therapies. Furthermore, few patients with glomerulonephritis or thrombotic microangiopathy secondary to treatment were reported. Hypertension is believed to be nitric oxide dependent, whereas proteinuria seems to be related to downregulation of podocyte tight junction protein. This article reviews data relating to hypertension and proteinuria associated with the use of these drugs.
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PMID:Angiogenesis inhibitor therapies: focus on kidney toxicity and hypertension. 1766 22

Independent of the association of obesity with dyslipidemia, hypertension, and increased propensity for diabetes, fatness per se is increasingly recognized as a cardiovascular offender. That adipose tissue releases a wide range of adipokines, growth factors, enzymes, and enzyme substrates linked to vascular injury provides a plausible explanation for the role of fat in vascular disease: tumor necrosis factor-alpha, leptin, resistin, interleukin-1, -6, -8, and -18, serum amyloid A, monocyte chemoattractant protein I, macrophage inhibitory factor, aortic carboxypeptidase, hepa-rin-binding epidermal growth factor-like growth factor, vascular endothelial growth factor, transforming growth factor beta, angiotensinogen, cathepsin S, estradiol, cortisol, mineralocorticoid releasing factor, and calcitonin peptides are probable fat-derived prothrombotic, proinflammatory, and proatherosclerotic agents acting in a paracrine and/or endocrine manner. Other adipocyte products such as adiponectin, transforming growth factor beta, and interleukin-10 exert some antiatherogenic effects. The following is a short overview of how adipose tissue products affect the vasculature.
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PMID:Fat cell-derived modulators of vascular cell pathophysiology: the list keeps growing. 1767 16

Angiotensin II can cause hypertension through enhanced vasoconstriction of renal vasculature. One proposed mechanism for reduction of angiotensin II-induced hypertension is through inhibition of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase cascade. MEK/ERK has been shown to phosphorylate the regulatory subunit of myosin light chain at identical positions as myosin light chain kinase. There are multiple mechanisms proposed regarding angiotensin II-mediated ERK activation. We hypothesized that renal microvascular smooth muscle cells (RmuVSMCs) signal through a unique pathway compared with thoracic aorta smooth muscle cells (TASMCs), which is involved in blood pressure regulation. Use of epidermal growth factor (EGF) and platelet derived growth factor (PDGF) receptor-specific inhibitors 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) and 6,7-dimethoxy-3-phenylquinoxaline (AG1296), respectively, demonstrates that angiotensin II activates ERK in TASMCs, but not RmuVSMCs, through transactivation of EGF and PDGF receptors. In addition, inhibition of Src with its specific inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d]pyrimidine (PP2) abolishes angiotensin II-, but not EGF-or PDGF-, mediated phosphorylation of ERK in RmuVSMCs, yet it has no effect in TASMCs. The physiological significance of transactivation was examined in vivo using anesthetized Wistar-Kyoto rats with 15 mg/kg 2'-amino-3'-methoxyflavone (PD98059), an MEK inhibitor, as well as 20 mg/kg AG1478 and 1.5 mg/kg AG1296 in an acute model of angiotensin II-mediated increase in blood pressure. None of the inhibitors had an effect on basal blood pressure, and only PD98059 reduced angiotensin II-mediated increase in blood pressure. Moreover, in RmuVSMCs, but not TASMCs, angiotensin II localizes phosphorylated ERK to actin filaments. In conclusion, angiotensin II signals through a unique mechanism in the renal vascular bed that may contribute to hypertension.
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PMID:Angiotensin II activates extracellular signal-regulated kinase independently of receptor tyrosine kinases in renal smooth muscle cells: implications for blood pressure regulation. 1791 76


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