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)

During the past several decades, the incidence of obesity has significantly increased worldwide. Enormous efforts have been devoted to understanding the molecular mechanisms underlying obesity and its related metabolic disorders such as type 2 diabetes, cardiovascular disease, atherosclerosis, and hypertension. It is now well-established that altered adipocyte metabolism in obese patients is closely associated with the induction of various metabolic stresses including hyperglycemia, hyperlipidemia, hyperinsulinemia, and chronic inflammation. However, the cellular factor(s) which sense metabolic changes and/or initiate the pathological progression of obesity-induced metabolic disorders remain to be elucidated. In this review, we will discuss the possible roles of cellular NADP(+)/NADPH, which function as redox potential regulators, in the induction of obesity-associated oxidative stress, chronic inflammation, and insulin resistance and suggest G6PD, a NADPH-generating enzyme, as a novel target for treating metabolic disorders.
 ...
PMID:New evaluations of redox regulating system in adipose tissue of obesity. 1745 57

Nonphagocytic NADPH oxidases have recently been suggested to play a major role in the regulation of physiological and pathophysiological processes, in particular, hypertrophy, remodeling, and angiogenesis in the systemic circulation. Moreover, NADPH oxidases have been suggested to serve as oxygen sensors in the lung. Chronic hypoxia induces vascular remodeling with medial hypertrophy leading to the development of pulmonary hypertension. We screened lung tissue for the expression of NADPH oxidase subunits. NOX1, NOXA1, NOXO1, p22phox, p47phox, p40phox, p67phox, NOX2, and NOX4 were present in mouse lung tissue. Comparing mice maintained for 21 days under hypoxic (10% O(2)) or normoxic (21% O(2)) conditions, an upregulation exclusively of NOX4 mRNA was observed under hypoxia in homogenized lung tissue, concomitant with increased levels in microdissected pulmonary arterial vessels. In situ hybridization and immunohistological staining for NOX4 in mouse lungs revealed a localization of NOX4 mRNA and protein predominantly in the media of small pulmonary arteries, with increased labeling intensities after chronic exposure to hypoxia. In isolated pulmonary arterial smooth muscle cells (PASMCs), NOX4 was localized primarily to the perinuclear space and its expression levels were increased after exposure to hypoxia. Treatment of PASMCs with siRNA directed against NOX4 decreased NOX4 mRNA levels and reduced PASMC proliferation as well as generation of reactive oxygen species. In lungs from patients with idiopathic pulmonary arterial hypertension (IPAH), expression levels of NOX4, which was localized in the vessel media, were 2.5-fold upregulated. These results support an important role for NOX4 in the vascular remodeling associated with development of pulmonary hypertension.
 ...
PMID:Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. 1767 80

NADPH oxidases have recently been shown to contribute to the pathogenesis of hypertension. The development of specific inhibitors of these enzymes has focused attention on their potential therapeutic use in hypertensive disease. Two of the most specific inhibitors, gp91ds-tat and apocynin, have been shown to decrease blood pressure in animal models of hypertension. Other inhibitors, including diphenylene iodonium, aminoethyl benzenesulfono fluoride, S17834, PR39, protein kinase C inhibitors, and VAS2870, have shown promise in vitro, but their in vivo specificity, pharmacokinetics, and effectiveness in hypertension remains to be determined. Of importance, the currently available antihypertensive agents angiotensin-converting enzyme inhibitors and angiotensin receptor blockers also effectively inhibit NADPH oxidase activation. Similarly, the cholesterol-lowering agents, statins, have been shown to attenuate NADPH oxidase activation. Although, antioxidants act to scavenge the reactive oxygen species produced by these enzymes, their effectiveness is limited. Targeting NADPH homologues may have a distinct advantage over current therapies because it would specifically prevent the pathophysiological formation of reactive oxygen species that contributes to hypertension.
 ...
PMID:NADPH oxidase inhibitors: new antihypertensive agents? 1766 10

1. It is well documented that the incidence and severity of several vascular diseases, such as hypertension, atherosclerosis and stroke, are lower in premenopausal women than men of similar age and post-menopausal women. The mechanisms responsible for gender differences in the incidence and severity of vascular disease are not well understood. However, emerging evidence suggests that sex hormone-dependent differences in vascular oxidative stress may play an important role. The aim of the present brief review is to provide an insight into the effect of gender and sex hormones on vascular oxidative stress. 2. When production of reactive oxygen species (ROS) is enhanced and/or their metabolism by anti-oxidant enzymes is impaired, a condition known as 'oxidative stress' can develop. Oxidative stress is believed to play an important role in both the initiation and progression of a variety of vascular diseases, including hypertension and atherosclerosis. NADPH oxidases are believed to be the major source of vascular ROS. Moreover, excessive production of ROS by NADPH oxidases has been linked to the development of vascular oxidative stress. 3. Increasing evidence suggests that levels of vascular ROS may be lower in women than men during health and disease. Indeed, the activity and expression of vascular NADPH oxidase is lower in female versus male animals under healthy, hypertensive and atherosclerotic conditions. 4. Gonadal sex hormones may play an important role in the regulation of vascular oxidative stress. For example, oestrogens, which are present in highest levels in premenopausal women, have been reported to lower vascular oxidative stress by modulating the expression and function of NADPH oxidases, as well as anti-oxidant enzymes. 5. Further studies are needed to clarify whether lower vascular oxidative stress in women in fact protects against the initiation and development of vascular disease and to further define the roles of gonadal sex hormones in such an effect. Knowledge gained from these studies may potentially lead to advances in the clinical diagnosis and treatment of vascular disease in both genders.
 ...
PMID:Effect of gender and sex hormones on vascular oxidative stress. 1771 91

Cardiac remodelling occurs in response to stress, such as chronic hypertension or myocardial infarction, and forms the substrate for subsequent development of heart failure. Key pathophysiological features include ventricular hypertrophy, interstitial fibrosis, contractile dysfunction, and chamber dilatation. Although the molecular mechanisms are complex and not fully defined, substantial evidence now implicates increased oxidative stress as being important. The NADPH oxidase ('Nox') enzymes are a particularly important source of reactive oxygen species that are implicated in redox signalling. This article reviews the evidence for an involvement of NADPH oxidases in different aspects of adverse cardiac remodelling. A better understanding of the roles of this complex enzyme family may define novel therapeutic targets for the prevention of heart failure.
 ...
PMID:Involvement of NADPH oxidases in cardiac remodelling and heart failure. 1790 89

1. The endothelin (ET) system and NADPH oxidase play important roles in the regulation of cardiovascular function, as well as in the pathogenesis of hypertension and other cardiovascular diseases. 2. Endothelins activate NADPH oxidases and thereby increase superoxide production, resulting in oxidative stress and cardiovascular dysfunction. Thus, NADPH oxidases may mediate the role of endothelins in some cardiovascular diseases. However, the role of reactive oxygen species (ROS) in mediating ET-induced vasoconstriction and cardiovascular disease remains under debate, as evidenced by conflicting reports from different research teams. Conversely, activation of NADPH oxidase can stimulate ET secretion via ROS generation, which further enhances the cardiovascular effects of NADPH oxidase. However, little is known about how ROS activate the endothelin system. It seems that the relationship between ET-1 and ROS may vary with cardiovascular disorders. 3. Endothelins activate NADPH oxidase via the ET receptor-proline-rich tyrosine kinase-2 (Pyk2)-Rac1 pathway. Rac1 is an important regulator of NADPH oxidase. There is ample evidence supporting direct stimulation by Rac1 of NADPH oxidase activity. In addition, Rac1-induced cardiomyocyte hypertrophy is mediated by the generation of ROS.
 ...
PMID:Endothelins and NADPH oxidases in the cardiovascular system. 1804 20

Studies of fracture repair have revealed that paracrine endothelial-mesenchymal interactions direct bone formation that restores osseous integrity. Angiogenic growth factors and specific members of the bone morphogenetic protein (BMP) family mediate these interactions. Recently, these same signals have been shown to be critical in the vascular pathobiology of hypertension, diabetes, and atherosclerosis. In the arterial vasculature, mechanical and inflammatory redox signals, characteristic of hypertension and diabetes have emerged as a secretagogues for BMP production-with downstream activation of endothelial NADPH oxidases (Nox). Preliminary data now indicate that the paracrine signals provided by BMP and reactive oxygen species augment aortic myofibroblast Msx2-Wnt signaling and matrix turnover. The net mural response to these stimuli promotes osteogenic differentiation of calcifying vascular cells, moreover, oxidation of vascular LDL cholesterol generates oxysterols that trigger Runx2 activity via hedgehog pathways. Thus, BMP, Wnt, and hedgehog gene expression programs-osteogenic pathways highly familiar to the bone biologist-are elaborated in the arterial vasculature via redox-regulated mechanisms. In the brief review, we recount mounting evidence that points to oxidative stress as a major contributor to the pathobiology of diabetic arterial calcification.
 ...
PMID:Vascular Bmp Msx2 Wnt signaling and oxidative stress in arterial calcification. 1805 36

Accumulating evidence demonstrates the involvement of oxidative stress in the pathophysiology of cardiovascular diseases. The molecular mechanisms accountable for the increased production of reactive oxygen species remain uncertain. Among others, NADPH oxidase is one of the most important sources of superoxide in vascular cells. Here we investigate the role of NF-kB in the regulation of p22(phox) subunit and NADPH oxidase activity, in human aortic smooth muscle cells. Overexpression of p65/RelA or IKKbeta up-regulated p22(phox) gene promoter activity. Transcription factor pull-down assays demonstrated the physical interaction of p65/RelA protein with predicted NF-kB binding sites. Real time PCR and Western blotting analysis showed that p22(phox) mRNA and protein expression are significantly down-regulated by NF-kB decoy oligodeoxynucleotides and N-alpha-tosyl-l-phenylalanine chloromethyl ketone (TPCK). Lucigenin-enhanced chemiluminescence assay revealed that NF-kB inhibitors reduce the NADPH-dependent superoxide production. Regulation of NADPH oxidase by NF-kB may represent a possible mechanism whereby pro-inflammatory factors induce oxidative stress in atherosclerosis, hypertension, diabetes, stroke or heart failure.
 ...
PMID:Regulation of NADPH oxidase subunit p22(phox) by NF-kB in human aortic smooth muscle cells. 1815 42

Oxidative stress plays a key role in the pathophysiology of several major cardiovascular diseases, including atherosclerosis, hypertension, heart failure, stroke and diabetes. ROS (reactive oxygen species) affect multiple tissues either directly or through NO depletion. ROS induce cardiovascular dysfunction by modulating cell contraction/dilation, migration, growth/apoptosis and extracellular matrix protein turnover, which contribute to vascular and cardiac remodelling. Of the several sources of ROS within the cardiovascular system, a family of multisubunit NADPH oxidases appears to be a predominant contributor of superoxide anion. Recent findings suggest a significant role of the genetic background in NADPH oxidase regulation. Common genetic polymorphisms within the promoter and exonic sequences of CYBA, the gene that encodes the p22(phox) subunit of NADPH oxidase, have been characterized in the context of cardiovascular diseases. This review aims to present the current state of research into these polymorphisms in their relationship to cardiovascular diseases.
 ...
PMID:NADPH oxidase CYBA polymorphisms, oxidative stress and cardiovascular diseases. 1818 11

Endothelial dysfunction comprising impairment of endothelium-dependent vasodilator function and increased endothelial activation contributes to the pathophysiology of cardiovascular diseases such as atherosclerosis, diabetic vasculopathy, heart failure and hypertension. The changes in endothelial phenotype in these conditions occur in response to diverse stimuli including inflammatory cytokines, activation of renin-angiotensin-aldosterone system, hyperlipidaemia, hyperglycemia, ischemia-reperfusion and mechanical forces. An increased production of reactive oxygen species (ROS), such as superoxide and H(2)O(2) is involved in the genesis of these alterations in endothelial phenotype. The NADPH oxidases, Nox2 and Nox4, are major sources of ROS in endothelial cells and are implicated both in vasodilator dysfunction and in the modulation of redox-sensitive signalling pathways that influence endothelial cytoskeletal organisation, adhesion molecule expression, permeability, growth, migration and other functions. NADPH oxidases appear to be especially important in redox signalling in that they are specifically activated by diverse agonists and regulate the activation of downstream protein kinases, transcription factors and other biological molecules. This review provides an overview of NADPH oxidase structure and regulation in endothelial cells and their role in pathophysiology, focussing particularly on endothelial activation.
 ...
PMID:NADPH oxidase-derived reactive oxygen species in the regulation of endothelial phenotype. 1827 82


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>