Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0042373 (vascular disease)
17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydrogen peroxide (H2O2) is produced by inflammatory and vascular cells and induces oxidative stress, which may contribute to vascular disease and endothelial cell dysfunction. In smooth muscle cells, H2O2 induces production of O2 by activating NADPH oxidase. However, the mechanisms whereby H2O2 induces oxidative stress in endothelial cells are not well understood, although O2 may play a role. Recent studies have documented increased O2 in endothelial cells exposed to H2O2 via uncoupled nitric oxide synthase (NOS) and NADPH oxidase under static conditions. To assess responses to H2O2 in porcine aortic endothelial cells (PAEC) under shearing conditions, a constant flow rate of 24. 4 ml/min was applied to produce physiologically relevant shear stress (8. 2 dynes/cm). Here we demonstrate that treatment with 100 muM H2O2 increases intracellular O2 levels in PAEC. In addition, we demonstrate that l-NAME, an inhibitor of NOS, and apocynin, an inhibitor of NADPH oxidase, reduced O2 levels in PAEC treated with H2O2 under physiologic shear suggesting that both NOS and NADPH oxidase contribute to H2O2-induced O2 in PAEC. Co-inhibition of NOS and NADPH oxidase also reduced intracellular O2 levels under shear. We conclude that H2O2-induced oxidative stress in endothelial cells exhibits increased intracellular O2 levels through NOS and NADPH oxidase under shear. The inhibition of NOS and NADPH with H2O2 exposure is nonlinear, suggesting some interdependent or compensating system within endothelial cells. These findings suggest a complex interaction between H2O2 and oxidant-generating enzymes that may contribute to endothelial dysfunction in cardiovascular diseases.
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PMID:Mechanisms of H2O2-induced oxidative stress in endothelial cells exposed to physiologic shear stress. 1723 44

Uncoupling of the endothelial nitric oxide synthase (eNOS) resulting in superoxide anion (O(2)(-)) formation instead of nitric oxide (NO) causes diabetic endothelial dysfunction. eNOS regulates mobilization and function of endothelial progenitor cells (EPCs), key regulators of vascular repair. We postulate a role of eNOS uncoupling for reduced number and function of EPC in diabetes. EPC levels in diabetic patients were significantly reduced compared with those of control subjects. EPCs from diabetic patients produced excessive O(2)(-) and showed impaired migratory capacity compared with nondiabetic control subjects. NOS inhibition with N(G)-nitro-l-arginine attenuated O(2)(-) production and normalized functional capacity of EPCs from diabetic patients. Glucose-mediated EPC dysfunction was protein kinase C dependent, associated with reduced intracellular BH(4) (tetrahydrobiopterin) concentrations, and reversible after exogenous BH(4) treatment. Activation of NADPH oxidases played an additional but minor role in glucose-mediated EPC dysfunction. In rats with streptozotocin-induced diabetes, circulating EPCs were reduced to 39 +/- 5% of controls and associated with uncoupled eNOS in bone marrow. Our results identify uncoupling of eNOS in diabetic bone marrow, glucose-treated EPCs, and EPCs from diabetic patients resulting in eNOS-mediated O(2)(-) production. Subsequent reduction of EPC levels and impairment of EPC function likely contributes to the pathogenesis of vascular disease in diabetes.
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PMID:Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. 1732 34

Vascular disease states are associated with endothelial dysfunction and increased production of reactive oxygen species (ROS) derived from vascular NADPH oxidases in both vascular smooth muscle cells (VSMCs) and endothelial cells. Recent evidence suggests an important role for VSMC NADPH oxidases in vascular ROS production. However, it is unclear whether increased NADPH oxidase activity in endothelial cells alone is sufficient to alter overall vascular ROS production and hemodynamics. We sought to address these questions using transgenic mice with endothelial-targeted overexpression of the catalytic subunit of NADPH oxidase, Nox2. Aortas of Nox2 transgenic (Nox2-Tg) mice had increased total Nox2 mRNA and protein levels compared with wild-type littermates. Both p22phox mRNA and protein levels were also significantly elevated in Nox2-Tg aortas. Aortic superoxide production was significantly increased in Nox2-Tg mice compared with wild-type, but this difference was abolished by endothelial removal. Superoxide dismutase inhibition increased superoxide release and levels of Mn superoxide dismutase protein were significantly elevated in aortas from Nox2-Tg mice compared with wild type. Increased ROS production from endothelial Nox2 overexpression led to increased endothelial nitric oxide synthase protein and extracellular signal-regulated kinase 1/2 phosphorylation in transgenic aortas. Basal blood pressure was similar, however the pressor responses to both acute and chronic angiotensin II administration were significantly increased in Nox2-Tg mice compared with wild type. These results demonstrate that endothelial-targeted Nox2 overexpression is sufficient to increase vascular NADPH oxidase activity, activate downstream signaling pathways, and potentiate the hemodynamic response to angiotensin II, despite compensatory increases in vascular antioxidant enzymes. Endothelial cell Nox2-containing NADPH oxidase plays an important functional role in vascular redox signaling.
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PMID:Endothelial Nox2 overexpression potentiates vascular oxidative stress and hemodynamic response to angiotensin II: studies in endothelial-targeted Nox2 transgenic mice. 1736 3

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.
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PMID:Effect of gender and sex hormones on vascular oxidative stress. 1771 91

NADPH oxidases are major sources of superoxide in the vascular wall. This study investigates the role of protein kinase C (PKC) in regulating gene expression of NADPH oxidases. Treatment of human umbilical vein endothelial cells (HUVEC) and HUVEC-derived EA.hy 926 endothelial cells with phorbol 12-myristate 13-acetate (PMA) or phorbol 12,13-dibutyrate led to a PKC-dependent biphasic expression of the gp91phox homolog Nox4. A downregulation of Nox4 was observed at 6 h and an upregulation at 48 h after phorbol ester treatment. The early Nox4 downregulation was associated with a reduced superoxide production, whereas the late Nox4 upregulation was accompanied by a clear enhancement of superoxide. PMA activated the PKC isoforms alpha and epsilon in HUVEC and EA.hy 926 cells. Knockdown of PKCepsilon by siRNA prevented the early downregulation of Nox4, whereas knockdown of PKCalpha selectively abolished the late Nox4 upregulation. Vascular endothelial growth factor (VEGF), which activates PKCalpha but not PKCepsilon in HUVEC, increased Nox4 expression without the initial downregulation. VEGF-induced Nox4 upregulation was associated with an enhanced proliferation and angiogenesis of HUVEC. Both effects could be reduced by inhibition of NADPH oxidase. Thus, a selective inhibition/knockdown of PKCalpha may represent a novel therapeutic strategy for vascular disease.
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PMID:Differential roles of PKCalpha and PKCepsilon in controlling the gene expression of Nox4 in human endothelial cells. 1829 Nov 20

The superoxide generating enzyme NADPH oxidase has received much attention as a major cause of oxidative stress underlying vascular disease. However, there is increasing evidence that oxidant signaling involving NADPH oxidase has other important roles in cell biology. Nox family proteins are the catalytic, electron-transporting subunits of the NADPH oxidase enzyme complex. It is now clear that reactive oxygen species (ROS) generated by NADPH oxidase participate in intracellular signaling processes that regulate cell differentiation and proliferation. These mechanisms are important in tissue repair and tumorigenesis, diverse conditions where cell proliferation is required, but when poorly controlled the generation of ROS is obviously detrimental. Indeed, NADPH oxidase-mediated cell proliferation has been observed in a wide range of cell types including those found in blood vessels, kidney, liver, skeletal muscle precursors, neonatal cardiac myocytes, lung epithelial cells, gastric mucosa, brain microglia, and a variety of cancer cells. NADPH oxidases act not as isolated elements downstream of a particular pathway, but rather may amplify multiple receptor tyrosine kinase-mediated processes by inhibiting protein tyrosine phosphatases. Therefore, NADPH oxidase-mediated redox signaling may represent a unique intracellular amplifier of diverse signaling pathways involved in tissue repair processes such as cell proliferation, wound healing, angiogenesis and fibrosis. Recent studies also suggest that NADPH oxidase is involved in differentiation of stem cells. As occurs in unresolved inflammation, however, hyperactivity of this enzyme system leads to tissue injury. Thus modulating NADPH oxidase may have significant impacts on regenerative medicine and tissue engineering, such as growing heart muscle.
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PMID:Regulation of cell proliferation by NADPH oxidase-mediated signaling: potential roles in tissue repair, regenerative medicine and tissue engineering. 1928 5

Advanced glycated end-product receptor 1 (AGER1) protects against vascular disease promoted by oxidants, such as advanced glycated end products (AGEs), via inhibition of reactive oxygen species (ROS). However, the specific AGEs, sources, and pathways involved remain undefined. The mechanism of cellular NADPH oxidase (NOX)-dependent ROS generation by defined AGEs, N(epsilon)-carboxymethyl-lysine- and methylglyoxal (MG)-modified BSA, was assessed in AGER1 overexpressing (AGER1(+) EC) or knockdown (sh-mRNA-AGER1(+) EC) human aortic endothelial (EC) and ECV304 cells, and aortic segments from old (18 mo) C57BL6-F(2) mice, propagated on low-AGE diet (LAGE), or LAGE supplemented with MG (LAGE+MG). Wild-type EC and sh-mRNA-AGER1(+) EC, but not AGER1(+) EC, had high NOX p47(phox) and gp91(phox) activity, superoxide anions, and NF-kappaB p65 nuclear translocation in response to MG and N(epsilon)-carboxymethyl-lysine. These events involved epidermal growth factor receptor-dependent PKC-delta redox-sensitive Tyr-311 and Tyr-332 phosphorylation and were suppressed in AGER1(+) ECs and enhanced in sh-mRNA-AGER1(+) ECs. Aortic ROS, PKC-delta Tyr-311, and Tyr-332 phosphorylation, NOX expression, and nuclear p65 in older LAGE+MG mice were significantly increased above that in age-matched LAGE mice, which had higher levels of AGER1. In conclusion, circulating AGEs induce NADPH-dependent ROS generation in vascular aging in both in vitro and in vivo models. Furthermore, AGER1 provides protection against AGE-induced ROS generation via NADPH.
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PMID:AGER1 regulates endothelial cell NADPH oxidase-dependent oxidant stress via PKC-delta: implications for vascular disease. 1995 85

Most current theories for the mechanism of hypoxic pulmonary vasoconstriction (HPV) include a role for reactive oxygen species and/or changes in redox regulation, but extreme controversy exists regarding which systems and redox changes mediate the HPV response. Nitric oxide (NO) appears to help to maintain low pulmonary arterial pressure, suppress HPV, and prevent the development of pulmonary hypertension. Our studies have found a key role for glucose-6-phosphate dehydrogenase in bovine pulmonary arterial smooth muscle functioning to maintain elevated levels of cytosolic NADPH which fuels the generation of vasodilator levels of hydrogen peroxide. HPV results from hypoxia removing vasodilation by peroxide. Decreased superoxide generation by Nox4 oxidase and its conversion to peroxide by Cu,Zn-SOD appear to be potential factors in sensing hypoxia, and decreased cGMP-associated vasodilation and removal of redox controlled vasodilator mechanisms by increased cytosolic NADPH may be key coordinators of the HPV response. Oxidant generation associated with vascular disease processes, including the removal of NO by superoxide, and attenuation of its ability to stimulate cGMP production by oxidation of the heme and thiols of soluble guanylate cyclase attenuate potential beneficial actions of NO on pulmonary arterial function. While pulmonary hypertension appears to have multiple poorly understood effects on redox-associated processes, potentially influencing responses to hypoxia and NO-cGMP signaling, much remains to be elucidated regarding how these processes may be important factors in the progression, expression and therapeutic treatment of pulmonary hypertension.
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PMID:Oxidant-redox regulation of pulmonary vascular responses to hypoxia and nitric oxide-cGMP signaling. 2016 May 35

Mammalian cells are capable of generating metabolites of oxygen, referred to as reactive oxygen species (ROS) via the action of several enzymes. In vascular cells, ROS are predominantly produced by the NADPH oxidases, uncoupled nitric oxide synthase, xanthine oxidase and by mitochondrial sources. In hypertension, ROS production by these sources is increased, and this not only contributes to hypertension, but also causes vascular disease and dysfunction. ROS production in other organs, particularly the kidney and the centers within the brain, likely participate in blood pressure regulation. Despite the wealth of data supporting a role of ROS in hypertension and other cardiovascular diseases, treatment with commonly employed antioxidants have failed, and in some cases have proven harmful, prompting a reconsideration of the concept of oxidative stress. Within the cell, ROS are produced locally and have important signaling roles, such that scavenging of these species by exogenous antioxidants is difficult and could produce untoward effects. In this article, we consider these tissues and discuss potential new approaches to treatment of "oxidative stress".
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PMID:Oxidative stress and hypertension. 2040 31

Elevated reactive oxygen species (ROS) formation in the vascular wall is a key feature of cardiovascular diseases and a likely contributor to oxidative stress, endothelial dysfunction and vascular inflammation. The NADPH oxidases are a family of ROS generating enzymes, of which four members (Nox1, Nox2, Nox4 and Nox5) are expressed in blood vessels. Numerous studies have demonstrated that expression and activity of at least two isoforms of NADPH oxidase - Nox1 and Nox2 - are up-regulated in animal models of hypertension, diabetes and atherosclerosis. However, these observations are merely suggestive of a role for NADPH oxidases in vessel pathology and by no means establish cause and effect. Furthermore, questions surrounding the specificity of current pharmacological inhibitors of NADPH oxidase mean that findings obtained with these compounds must be viewed with caution. Here, we review the literature on studies utilising genetically-modified mouse strains to investigate the roles of NADPH oxidases in experimental models of vascular disease. While several studies on transgenic over-expressing or knockout mice support roles for Nox1- and/or Nox2-containing oxidases as sources of excessive vascular ROS production and causes of endothelial dysfunction in hypertension, atherosclerosis and diabetes, there are still no published reports on the effects of genetic modification of Nox4 or Nox5 in vascular or indeed any other contexts. Further understanding of the roles of specific isoforms of NADPH oxidase in vascular (patho)physiology should provide direction for future programs aimed at developing selective inhibitors of these enzymes as novel therapeutics in cardiovascular disease.
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PMID:Nox isoforms in vascular pathophysiology: insights from transgenic and knockout mouse models. 2050 Sep 86


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