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)

Accumulating evidence strongly implicates angiotensin II (AngII) intracellular signaling in mediating cardiovascular diseases such as hypertension, atherosclerosis and restenosis after vascular injury. In vascular smooth muscle cells (VSMCs), through its G-protein-coupled AngII Type 1 receptor (AT(1)), AngII activates various intracellular protein kinases, such as receptor or non-receptor tyrosine kinases, which includes epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), c-Src, PYK2, FAK, JAK2. In addition, AngII activates serine/threonine kinases such as mitogen-activated protein kinase (MAPK) family, p70 S6 kinase, Akt/protein kinase B and various protein kinase C isoforms. In VSMCs, AngII also induces the generation of intracellular reactive oxygen species (ROS), which play critical roles in activation and modulation of above signal transduction. Less is known about endothelial cell (EC) AngII signaling than VSMCs, however, recent studies suggest that endothelial AngII signaling negatively regulates the nitric oxide (NO) signaling pathway and thereby induces endothelial dysfunction. Moreover, in both VSMCs and ECs, AngII signaling cross-talk with insulin signaling might be involved in insulin resistance, an important risk factor in the development of cardiovascular diseases. In fact, clinical and pharmacological studies showed that AngII infusion induces insulin resistance and AngII converting enzyme inhibitors and AT(1) receptor blockers improve insulin sensitivity. In this review, we focus on the recent findings that suggest the existence of novel signaling mechanisms whereby AngII mediates processes, such as activation of receptor or non-receptor tyrosine kinases and ROS, as well as cross-talk between insulin and NO signal transduction in VSMCs and ECs.
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PMID:Angiotensin II regulates vascular and endothelial dysfunction: recent topics of Angiotensin II type-1 receptor signaling in the vasculature. 1647 78

Advances in chemotherapeutic agents have led to improved outcomes for patients with metastatic colorectal cancer (CRC). Chemotherapies, however, are limited by their toxicities and lack of specificity. Aberrations in the regulation and expression of growth factors have been implicated in the development of CRC, and this understanding has led to the development of targeted agents. In 2004, two novel agents, bevacizumab and cetuximab, were approved by the US Food and Drug Administration for the treatment of metastatic CRC. Bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor, and cetuximab, a human-mouse chimeric monoclonal antibody to the epidermal growth factor receptor, have changed the field dramatically. Bevacizumab appears to augment the efficacy of combination chemotherapy regimens for the treatment of metastatic CRC in both the first- and second-line settings, and the role of bevacizumab as part of adjuvant treatment is the subject of ongoing trials. However, because of the increased incidence of serious arterial thromboembolic events, gastrointestinal perforations, bleeding complications, and hypertension associated with bevacizumab, this agent is probably not indicated in all circumstances. Combination treatment with cetuximab and irinotecan appears appropriate in patients with advanced CRC who have failed irinotecan. Patients who are unable to receive additional irinotecan may be treated with cetuximab monotherapy. Positive epidermal growth factor receptor status by immunohistochemistry of a tumor specimen is presently mandated to determine candidacy for this therapy, although this assay appears to be suboptimal and newer assessment techniques to determine suitability for therapy must be developed. Phase III trials should shed light on the role of cetuximab in the first-line metastatic and adjuvant settings. Multitargeted strategies in CRC combining chemotherapy with bevacizumab and cetuximab are currently being explored. Further advances in the treatment of CRC are expected through continued scientific investigation and well-designed clinical trials.
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PMID:Targeted therapy in colorectal cancer. 1672 21

Mechanical factors regulate both blood vessel growth and the development and progression of vascular disease. Acting on apoptotic and inflammatory signaling, the transcription factor nuclear factor kappaB (NF-kappaB) is a likely mediator of these processes. Nevertheless, pressure-dependent NF-kappaB activation pathways remain mostly unknown. Here we report that high intraluminal pressure induces reactive oxygen species (ROS) in arteries and that inhibition of NADPH oxidase prevents both the generation of ROS and the activation of NF-kappaB associated with high pressure. We also identify the epidermal growth factor receptor (EGFR) as a ROS-dependent signaling intermediate. In arteries from EGFR mutant mice (waved-2), pressure fails to activate NF-kappaB. Moreover, using vessels from EGFR ligand-deficient mice, we show that transforming growth factor (TGF)-alpha, but neither heparin-binding EGF-like growth factor nor epiregulin, transduces NF-kappaB activation by high pressure. Preventing the release of the active form of TGF-alpha also abolishes NF-kappaB induction by strain. The role of TGF-alpha signaling in vascular remodeling is substantiated in vivo; angiotensin II-induced activation of NF-kappaB and associated cell proliferation and wall thickening are much reduced in TGF-alpha-mutant mice compared with wild-type, despite equivalent hypertension in both groups. Conversely, apoptotic cells are detected only in vessels from hypertensive TGF-alpha-mutant mice, outlining the role of NF-kappaB in cell survival. Finally, the NF-kappaB activation pathway contrasts with that of extracellular signal-regulated kinase 1/2, which is activated by stretch through the EGFR but does not implicate TGF-alpha. Hence, our data identify TGF-alpha as a potential specific target to modulate mechanosensitive NF-kappaB activation and associated vascular remodeling.
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PMID:Transforming growth factor-alpha mediates nuclear factor kappaB activation in strained arteries. 1691 2

Ascochlorin is a prenyl-phenol compound that was isolated from the fungus Ascochyta viciae. Ascochlorin reduces serum cholesterol and triglyceride levels, suppresses hypertension and tumor development, and ameliorates type I and II diabetes. Here, to better understand the mechanisms by which ascochlorin regulates physiological or pathological events and induces responses in the pharmacological treatment of cancer, we performed differential analysis of the proteome of the human osteosarcoma cells U2OS in response to ascochlorin. In addition, we established the first two-dimensional map of the U2OS proteome. The U2OS cell proteomes with and without treatment with ascochlorin were compared using two-dimensional electrophoresis, matrix-assisted laser desorption/ionization mass spectrometry and bioinformatics. The largest differences in expression were observed for the epidermal growth factor receptor (4-fold decrease), ribulose-5-phosphate-epimerase (13-fold decrease), ATP-dependent RNA helicase (8-fold decrease), and kelch-like ECH-associated protein 1 (6-fold decrease). The abundance of heterogeneous nuclear ribonucleoprotein L and minichromosome maintenance protein 7 increased 12- and 8.2-fold, respectively. In addition, Erk 2 was increased 3-fold in U2OS cells treated with ascochlorin. The expression of some selected proteins was confirmed by western blotting, zymography and RT-PCR analysis.
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PMID:Proteome analysis of responses to ascochlorin in a human osteosarcoma cell line by 2-D gel electrophoresis and MALDI-TOF MS. 1702 33

Preeclampsia is a pregnancy specific disorder characterised by hypertension and proteinuria occurring after the twentieth week of gestation. Preeclampsia induced hypertension is the result of increased vascular reactivity and endothelial dysfunction, however, the mechanisms underlying this state remain elusive. One possible mediator may be the matrix metalloproteinases (MMPs), a family of proteinases typically recognized for long term tissue remodelling. This review examines the evidence suggesting a role for MMPs in acutely regulating vascular function. Studies have shown that MMPs can activate vasoconstrictors (e.g. endothelin), inactivate vasodilators (e.g. calcitonin gene related peptide) and transactivate cell surface receptors responsible for vasoconstriction (e.g. epidermal growth factor receptor). The potential role of these proteinases in preeclampsia will then be discussed.
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PMID:Matrix metalloproteinases: control of vascular function and their potential role in preeclampsia. 1712 57

Antiangiogenic therapy has emerged as an important concept in the treatment of solid tumors, including non-small cell lung cancer (NSCLC). Vascular endothelial growth factor (VEGF) represents an important therapeutic target, as it is the primary mediator of angiogenesis and is induced by multiple tumor-relevant stimuli. The anti-VEGF monoclonal antibody bevacizumab has demonstrated a significant clinical benefit in patients with non-squamous cell NSCLC in a randomized phase III trial. The addition of bevacizumab to chemotherapy with paclitaxel plus carboplatin provided a significant survival benefit over chemotherapy alone. Bevacizumab is associated with an increased risk of severe bleeding; thus, patients should be carefully selected for bevacizumab treatment. Hypertension is also seen with bevacizumab but can be managed with antihypertensive agents. Ongoing studies are evaluating bevacizumab in other NSCLC settings and are attempting to identify predictive factors for responses to bevacizumab. Antiangiogenic approaches other than bevacizumab are also being investigated, including several small-molecule tyrosine kinase inhibitors that have demonstrated activity in small studies. In some cases, combination therapy with different targeted agents may provide the most comprehensive treatment approach. In a randomized phase II study, bevacizumab in combination with the epidermal growth factor receptor inhibitor erlotinib demonstrated efficacy similar to chemotherapy plus bevacizumab. Ongoing studies are continuing to investigate new agents and identify the patients most likely to benefit from antiangiogenic therapy.
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PMID:Angiogenesis inhibition in the treatment of lung cancer. 1714 57

We have observed recently that experimental renal failure in the rat is accompanied by increases in circulating concentrations of the cardiotonic steroid, marinobufagenin (MBG), and substantial cardiac fibrosis. We performed the following studies to examine whether MBG might directly stimulate cardiac fibroblast collagen production. In vivo studies were performed using the 5/6th nephrectomy model of experimental renal failure (PNx), MBG infusion (MBG), PNx after immunization against MBG, and concomitant PNx and adrenalectomy. Physiological measurements with a Millar catheter and immunohistochemistry were performed. In vitro studies were then pursued with cultured isolated cardiac fibroblasts. We observed that PNx and MBG increased MBG levels, blood pressure, heart size, impaired diastolic function, and caused cardiac fibrosis. PNx after immunization against MBG and concomitant PNx and adrenalectomy had similar blood pressure as PNx but less cardiac hypertrophy, diastolic dysfunction, and cardiac fibrosis. MBG induced increases in procollagen-1 expression by cultured cardiac fibroblasts at 1 nM concentration. These increases in procollagen expression were accompanied by increases in collagen translation and increases in procollagen-1 mRNA without any demonstrable increase in procollagen-1 protein stability. The stimulation of fibroblasts with MBG could be prevented by administration of inhibitors of tyrosine phosphorylation, Src activation, epidermal growth factor receptor transactivation, and N-acetyl cysteine. Based on these findings, we propose that MBG directly induces increases in collagen expression by fibroblasts, and we suggest that this may be important in the cardiac fibrosis seen with experimental renal failure.
Hypertension 2007 Jan
PMID:Marinobufagenin stimulates fibroblast collagen production and causes fibrosis in experimental uremic cardiomyopathy. 1714 84

The intracellular signal transduction of AngII (angiotensin II) has been implicated in cardiovascular diseases, such as hypertension, atherosclerosis and restenosis after injury. AT(1) receptor (AngII type-1 receptor), a G-protein-coupled receptor, mediates most of the physiological and pathophysiological actions of AngII, and this receptor is predominantly expressed in cardiovascular cells, such as VSMCs (vascular smooth muscle cells). AngII activates various signalling molecules, including G-protein-derived second messengers, protein kinases and small G-proteins (Ras, Rho, Rac etc), through the AT(1) receptor leading to vascular remodelling. Growth factor receptors, such as EGFR (epidermal growth factor receptor), have been demonstrated to be 'trans'-activated by the AT(1) receptor in VSMCs to mediate growth and migration. Rho and its effector Rho-kinase/ROCK are also implicated in the pathological cellular actions of AngII in VSMCs. Less is known about the endothelial AngII signalling; however, recent studies suggest the endothelial AngII signalling positively, as well as negatively, regulates the NO (nitric oxide) signalling pathway and, thereby, modulates endothelial dysfunction. Moreover, selective AT(1)-receptor-interacting proteins have recently been identified that potentially regulate AngII signal transduction and their pathogenic functions in the target organs. In this review, we focus our discussion on the recent findings and concepts that suggest the existence of the above-mentioned novel signalling mechanisms whereby AngII mediates the formation of cardiovascular diseases.
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PMID:Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology. 1734 43

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

Aldosterone concentrations are inappropriately high in many patients with hypertension, as well as in an increasing number of individuals with metabolic syndrome and sleep apnoea. A growing body of evidence suggests that aldosterone and/or activation of the MR (mineralocorticoid receptor) contributes to cardiovascular remodelling and renal injury in these conditions. In addition to causing sodium retention and increased blood pressure, MR activation induces oxidative stress, endothelial dysfunction, inflammation and subsequent fibrosis. The MR may be activated by aldosterone and cortisol or via transactivation by the AT(1) (angiotenin II type 1) receptor through a mechanism involving the EGFR (epidermal growth factor receptor) and MAPK (mitogen-activated protein kinase) pathway. In addition, aldosterone can generate rapid non-genomic effects in the heart and vasculature. MR antagonism reduces mortality in patients with CHF (congestive heart failure) and following myocardial infarction. MR antagonism improves endothelial function in patients with CHF, reduces circulating biomarkers of cardiac fibrosis in CHF or following myocardial infarction, reduces blood pressure in resistant hypertension and decreases albuminuria in hypertensive and diabetic patients. In contrast, whereas adrenalectomy improves glucose homoeostasis in hyperaldosteronism, MR antagonism may worsen glucose homoeostasis and impairs endothelial function in diabetes, suggesting a possible detrimental effect of aldosterone via non-genomic pathways.
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PMID:Aldosterone and end-organ damage. 1768 82


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