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)

Heme oxygenase-1 (HO-1) induction can attenuate the development of angiotensin II (ANG II)-dependent hypertension. However, the mechanism by which HO-1 lowers blood pressure in this model is not clear. The goal of this study was to test the hypothesis that induction of HO-1 in the kidney can attenuate the increase in reactive oxygen species (ROS) generation in the kidney that occurs during ANG II-dependent hypertension. Mice were divided into four groups, control (Con), cobalt protoporphyrin (CoPP), ANG II, and ANG II + CoPP. CoPP treatment (50 mg/kg) was administered in a single subcutaneous injection 2 days prior to implantation of an osmotic minipump that infused ANG II at a rate of 1 microg x kg(-1) x min(-1). At the end of this period, mean arterial blood pressure (MAP) averaged 93 +/- 5, 90 +/- 5, 146 +/- 8, and 105 +/- 6 mmHg in Con, CoPP-, ANG II-, and ANG II + CoPP-treated mice. To determine whether HO-1 induction resulted in a decrease in ANG II-stimulated ROS generation in the renal medulla, superoxide production was measured. Medullary superoxide production was increased by ANG II infusion and normalized in mice pretreated with CoPP. The reduction in ANG II-mediated superoxide production in the medulla with CoPP was associated with a decrease in extracellular superoxide dismutase protein but an increase in catalase protein and activity. These results suggest that reduction in superoxide and possibly hydrogen peroxide production in the renal medulla may be a potential mechanism by which induction of HO-1 with CoPP lowers blood pressure in ANG-II dependent hypertension.
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PMID:HO-1 induction lowers blood pressure and superoxide production in the renal medulla of angiotensin II hypertensive mice. 1719 25

Pulmonary hypertension is a life-threatening disease process that affects adults and children. Pediatric patients with lung diseases that can be complicated by alveolar hypoxia, such as bronchopulmonary dysplasia (BPD), are at risk for developing pulmonary hypertension, which leads to right heart failure and greatly increases morbidity and mortality. We review the evidence that reactive oxygen species (ROS) are generated by pulmonary vascular wall cells in response to a hypoxic exposure, and that this response contributes to chronic hypoxic pulmonary hypertension. We summarize the accumulating data implicating NADPH oxidase as a major source of O2 responsible for vascular remodeling and hypertension. We also consider the effects of chronic hypoxia on the clearance of O2 by superoxide dismutases, specifically extracellular superoxide dismutase, which is highly expressed in the pulmonary artery. We review the role of the activated vascular adventitial fibroblast in the generation of ROS and in the pathogenesis of vascular remodeling, and provide a rationale to consider the role of the activated fibroblast and ROS in hypoxic pulmonary hypertension using a clinically relevant bovine model of neonatal chronic hypoxic pulmonary hypertension.
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PMID:Role of reactive oxygen species in chronic hypoxia-induced pulmonary hypertension and vascular remodeling. 1826 91

The extracellular superoxide dismutase (SOD3), a secretory copper-containing enzyme, regulates angiotensin II (Ang II)-induced hypertension by modulating levels of extracellular superoxide anion. The present study was designed to determine the role of the copper transporter Menkes ATPase (MNK) in Ang II-induced SOD3 activity and hypertension in vivo. Here we show that chronic Ang II infusion enhanced systolic blood pressure and vascular superoxide anion production in MNK mutant (MNK(mut)) mice as compared with those in wild-type mice, which are associated with impaired acetylcholine-induced endothelium-dependent vasorelaxation in MNK(mut) mice. These effects in MNK(mut) mice are rescued by infusion of the SOD mimetic Tempol. By contrast, norepinephrine-induced hypertension, which is not associated with an increase in vascular superoxide anion production, is not affected in MNK(mut) mice. Mechanistically, basal and Ang II infusion-induced increase in vascular SOD3-specific activity is significantly inhibited in MNK(mut) mice. Coimmunoprecipitation analysis reveals that Ang II stimulation promotes association of MNK with SOD3 in cultured vascular smooth muscle cell and in mouse aortas, which may contribute to SOD3-specific activity by increasing copper delivery to SOD3 through MNK. In summary, MNK plays an important role in modulating Ang II-induced hypertension and endothelial function by regulating SOD3 activity and vascular superoxide anion production and becomes a potential therapeutic target for oxidant stress-dependent cardiovascular diseases.
Hypertension 2008 Nov
PMID:Role of Menkes ATPase in angiotensin II-induced hypertension: a key modulator for extracellular superoxide dismutase function. 1876 96

Paul Vanhoutte is one of the fathers of vascular biology. Among his great contributions, he demonstrated that endothelium modulates vasomotor response to vasoactive products (including serotonin) that are released when platelets aggregate in an artery. He found in arteries ex vivo that when endothelium is dysfunctional, in atherosclerosis or hypertension, normal relaxation to aggregation of platelets is impaired and vessels may contract. He proposed that this mechanism may predispose to vasospasm. The results of our experiments in vivo indicate that atherosclerosis greatly potentiates vasoconstrictor responses to serotonin in the limb, brain, and eye of monkeys. We proposed that transient ischemic attacks may be mediated by platelet-induced vasospasm. We observed endothelial dysfunction in atherosclerotic monkeys, with improvement of endothelial function when hypercholesterolemia was corrected. Recently, we studied the aortic valve, which has unique endothelium, in hypercholesterolemic mice to examine the pathophysiology of aortic valvular stenosis. Oxidative stress is increased in stenotic valves, and severe aortic stenosis develops in about one third of old, hypercholesterolemic mice. In stenotic aortic valves from humans, there is increased oxidative stress near calcified regions of the valves. Oxidative stress may trigger expression of pro-calcific genes in the aortic valve. Finally, we have used gene transfer of extracellular superoxide dismutase (ecSOD) to study endothelial effects of oxidative stress. Gene transfer of normal ecSOD improves endothelial dysfunction in several disease states, but gene transfer of ecSOD(R213G), a gene variant of ecSOD that is common in humans, fails to improve endothelial function. Gene transfer approaches may be useful to study mechanisms by which gene variants predispose to endothelial dysfunction and vascular disease.
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PMID:Endothelial function in the time of the giants. 1903 17

The circumventricular organs (CVOs) lack a well-formed blood-brain barrier and produce superoxide in response to angiotensin II and other hypertensive stimuli. This increase in central superoxide has been implicated in the regulation of blood pressure. The extracellular superoxide dismutase (SOD3) is highly expressed in cells associated with CVOs and particularly with tanycytes lining this region. To understand the role of SOD3 in the CVOs in blood pressure regulation, we performed intracerebroventricular injection an adenovirus encoding Cre-recombinase (5x10(8) particles per milliliter) in mice with loxP sites flanking the SOD3 coding region (SOD3(loxp/loxp) mice). An adenovirus encoding red-fluorescent protein was injected as a control. Deletion of CVO SOD3 increased baseline blood pressure modestly and markedly augmented the hypertensive response to low-dose angiotensin II (140 ng/kg per day), whereas intracerebroventricular injection of adenovirus encoding red-fluorescent protein had minimal effects on these parameters. Adenovirus encoding Cre-recombinase-treated mice exhibited increased sympathetic modulation of heart rate and blood pressure variability, increased vascular superoxide production, and T-cell activation as characterized by increased circulating CD69(+)/CD3(+) cells. Deletion of CVO SOD3 also markedly increased vascular T-cell and leukocyte infiltration caused by angiotensin II. We conclude that SOD3 in the CVO plays a critical role in the regulation of blood pressure, and its loss promotes T-cell activation and vascular inflammation, in part by modulating sympathetic outflow. These findings provide insight into how central signals produce vascular inflammation in response to hypertensive stimuli, such as angiotensin II.
Hypertension 2010 Feb
PMID:Induction of hypertension and peripheral inflammation by reduction of extracellular superoxide dismutase in the central nervous system. 2000 74

Angiotensin II (Ang II) produces oxidative stress and endothelial dysfunction in blood vessels. The vasculature from females may be protected against deleterious effects of Ang II. We tested the hypothesis that manganese superoxide dismutase (MnSOD) protects against Ang II-induced endothelial dysfunction. Experiments were performed in C57Bl/6, wild-type (MnSOD(+/+)), and MnSOD-deficient (MnSOD(+/-)) mice treated systemically with vehicle or Ang II. Basilar arteries were isolated from mice treated for 1 week with a nonpressor dose of Ang II (0.28 mg/kg per day). Ang II treatment produced superoxide-mediated impairment of responses to the endothelium-dependent vasodilator acetylcholine (P<0.05). In male but not female MnSOD(+/+) mice, Ang II modestly inhibited responses to acetylcholine (P<0.05). In contrast, Ang II selectively impaired these responses by up to 70% in male MnSOD(+/-) mice (P<0.05), and this effect was reversed by Tempol (P<0.05). Ang II had no effect on acetylcholine responses in MnSOD(+/-) female mice. Vascular superoxide levels after treatment with an inhibitor of CuZn and extracellular superoxide dismutase were higher in Ang II-treated versus vehicle-treated MnSOD(+/-) mice. Thus, a nonpressor dose of Ang II produces endothelial dysfunction in male mice only, suggesting that the female vasculature is protected from Ang II. In male but not female mice, MnSOD deficiency enhanced endothelial dysfunction, suggesting that MnSOD normally protects the vasculature during disease states in which Ang II contributes to vascular dysfunction.
Hypertension 2010 Apr
PMID:Sex differences in protection against angiotensin II-induced endothelial dysfunction by manganese superoxide dismutase in the cerebral circulation. 2019 98

Previous studies indicate that superoxide is important in the modulation of blood pressure but have not specifically identified the cell types or organs involved. We created mice with loxP sites flanking the extracellular superoxide dismutase (SOD3) gene. These mice were crossed with mice expressing inducible Cre-recombinase driven by the smooth muscle myosin heavy chain promoter allowing tissue-specific deletion of SOD3. Deletion of SOD3 increased vascular superoxide and reduced vascular NO levels as detected by electron spin resonance. Despite these changes in NO and superoxide, we did not observe increases in vascular inflammation caused by angiotensin II. Moreover, deletion of vascular SOD3 did not augment hypertension in response to angiotensin II. In additional studies, we also deleted SOD3 from the circumventricular organs by intracerebroventricular injection of an adenovirus encoding Cre-recombinase. Although this raised blood pressure and augmented the hypertension caused by angiotensin II, these responses were not further increased by vascular deletion of SOD3. These data suggest that the extracellular superoxide dismutase in vascular smooth muscle is not involved in the genesis of angiotensin II-induced hypertension and further emphasize the role of central SOD3 in the modulation of blood pressure.
Hypertension 2011 Aug
PMID:Role of vascular extracellular superoxide dismutase in hypertension. 2173 Feb 94

Exposure of newborn calves to chronic hypoxia causes pulmonary artery (PA) hypertension and remodeling. Previous studies showed that the redox-sensitive transcription factor, early growth response-1 (Egr-1), is upregulated in the PA of chronically hypoxic calves and regulates cell proliferation. Furthermore, we established in mice a correlation between hypoxic induction of Egr-1 and reduced activity of extracellular superoxide dismutase (EC-SOD), an antioxidant that scavenges extracellular superoxide. We now hypothesize that loss of EC-SOD in chronically hypoxic calves leads to extracellular superoxide-mediated upregulation of Egr-1. To validate our hypothesis and identify the signaling pathways involved, we utilized PA tissue from normoxic and chronically hypoxic calves and cultured calf and human PA smooth muscle cells (PASMC). Total SOD activity was low in the PA tissue, and only the extracellular SOD component decreased with hypoxia. PA tissue of hypoxic calves showed increased oxidative stress and increased Egr-1 mRNA. To mimic the in vivo hypoxia-induced extracellular oxidant imbalance, cultured calf PASMC were treated with xanthine oxidase (XO), which generates extracellular superoxide and hydrogen peroxide. We found that 1) XO increased Egr-1 mRNA and protein, 2) XO induced the phosphorylation of ERK1/2 and, 3) pretreatment with an ERK1/2 inhibitor prevented induction of Egr-1 by XO. siRNA knock-down of EC-SOD in human PASMC also upregulated Egr-1 mRNA and protein, activated ERK1/2, and enhanced SMC proliferation and reduced apoptosis. We conclude that an oxidant/antioxidant imbalance arising from loss of EC-SOD in the PA with chronic hypoxia induces Egr-1 via activation of ERK1/2 and contributes to pulmonary vascular remodeling.
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PMID:Xanthine oxidase-derived ROS upregulate Egr-1 via ERK1/2 in PA smooth muscle cells; model to test impact of extracellular ROS in chronic hypoxia. 2214 Apr 45

Toll-like receptor 4 (TLR4) and angiotensin II (AngII) induce vascular remodeling through the production of reactive oxygen species (ROS). AngII has also been shown to increase antioxidant enzyme extracellular superoxide dismutase (ecSOD). However, the roles of TLR4 in Ang II-induced ROS production, vascular remodeling and hypertension remain unknown. Mice lacking TLR4 function showed significant inhibition of vascular remodeling in response to chronic AngII infusion, with no impact on blood pressure. The increases in ROS level and NADPH oxidase activity in response to AngII infusion were markedly blunted in TLR4-deficient mice. Similar effects were observed in wild-type (WT) mice treated with a sub-depressor dose of the AT1 receptor antagonist irbesartan, which had no effects on TLR4-deficient mice. Intriguingly, the AngII infusion-induced increases in ecSOD activity and expression were rather enhanced in TLR4-deficient mice compared with WT mice, whereas the expression of the proinflammatory chemokine MCP-1 was decreased. Importantly, AngII-induced vascular remodeling was positively correlated with NADPH oxidase activity, ROS levels and MCP-1 expression levels. Notably, chronic norepinephrine infusion, which elevates blood pressure without increasing ROS production, did not induce significant vascular remodeling in WT mice. Taken together, these findings suggest that ROS elevation is required for accelerating vascular remodeling but not for hypertensive effects in this model. We demonstrated that TLR4 plays a pivotal role in regulating AngII-induced vascular ROS levels by inhibiting the expression and activity of the antioxidant enzyme ecSOD, as well as by activating NADPH oxidase, which enhances inflammation to facilitate the progression of vascular remodeling.
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PMID:TLR4 is a critical regulator of angiotensin II-induced vascular remodeling: the roles of extracellular SOD and NADPH oxidase. 2599 4

Epigenetic mechanisms, including DNA methylation and histone acetylation, regulate gene expression in idiopathic pulmonary arterial hypertension (IPAH). These mechanisms can modulate expression of extracellular superoxide dismutase (SOD3 or EC-SOD), a key vascular antioxidant enzyme, and loss of vascular SOD3 worsens outcomes in animal models of pulmonary arterial hypertension. We hypothesized that SOD3 gene expression is decreased in patients with IPAH due to aberrant DNA methylation and/or histone deacetylation. We used lung tissue and pulmonary artery smooth muscle cells (PASMC) from subjects with IPAH at transplantation and from failed donors (FD). Lung SOD3 mRNA expression and activity was decreased in IPAH vs. FD. In contrast, mitochondrial SOD (Mn-SOD or SOD2) protein expression was unchanged and intracellular SOD activity was unchanged. Using bisulfite sequencing in genomic lung or PASMC DNA, we found the methylation status of the SOD3 promoter was similar between FD and IPAH. Furthermore, treatment with 5-aza-2'-deoxycytidine did not increase PASMC SOD3 mRNA, suggesting DNA methylation was not responsible for PASMC SOD3 expression. Though total histone deacetylase (HDAC) activity, histone acetyltransferase (HAT) activity, acetylated histones, and acetylated SP1 were similar between IPAH and FD, treatment with two selective class I HDAC inhibitors increased SOD3 only in IPAH PASMC. Class I HDAC3 siRNA also increased SOD3 expression. Trichostatin A, a pan-HDAC inhibitor, decreased proliferation in IPAH, but not in FD PASMC. These data indicate that histone deacetylation, specifically via class I HDAC3, decreases SOD3 expression in PASMC and HDAC inhibitors may protect IPAH in part by increasing PASMC SOD3 expression.
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PMID:Histone deacetylation contributes to low extracellular superoxide dismutase expression in human idiopathic pulmonary arterial hypertension. 2723 98


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