Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001486 (Adenovirus)
 3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypertension is a major risk factor in the development of cardiovascular disease. Adenovirus gene transfer of endothelin-1 (Ad.CMV.ET-1) in rats produced significant (5-fold) increases in plasma ET-1 and systemic blood pressure (46%) 4 days after viral administration, compared with beta-galactosidase (Ad.CMV.beta-gal) injected as control. The density (B(max)) of the ET receptor ET(A) measured in aortas was reduced significantly by more than 50% to 17+/-2 fmol.mg(-1) of protein for the Ad.CMV.ET-1 group compared with 39+/-6 fmol x mg(-1) of protein for the control. There was no change in the density of the smaller population of the ET(B) sub-type. In agreement, the ratio of ET(A) mRNA to cyclophilin mRNA (a housekeeping gene) measured by Northern analysis was reduced in Ad.CMV.ET-1 rats compared with controls. The ratio of mRNA encoding the ET(B) sub-type did not change. ET-1 vasoconstriction was significantly reduced (P<0.05) in aortas from Ad.CMV.ET-1-treated rats [pD(2)=8.67+/-0.14 (where pD(2) is -log(10)EC(50)); n=11] versus the control (pD(2)=9.11+/-0.06; n=14) but there was no significant difference in the potency of two other vasoconstrictors tested (noradrenaline and Arg-vasopressin), indicating this was a specific effect on ET receptors. There was no change in the affinity of ET-1 binding to either receptor sub-type in the experimental group compared with the control, demonstrating that the attenuation in the constrictor response is the result of the reduced density of receptors rather than a change in affinity. The results show that ET(A) (but not ET(B)) receptors are modulated in this experimental model of hypertension and provide further evidence for selective blockade of the ET(A) receptor as a therapeutic strategy.
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PMID:Elevated systemic levels of endothelin-1 and blood pressure correlate with blunted constrictor responses and downregulation of endothelin(A), but not endothelin(B), receptors in an animal model of hypertension. 1219 22

Obesity, i.e. an excess of white adipose tissue (WAT), predisposes to the development of type 2 diabetes and cardiovascular disease. Brown adipose tissue is present in rodents but not in adult humans. It expresses uncoupling protein 1 (UCP1) that allows dissipation of energy as heat. Peroxisome proliferator-activated receptor gamma (PPAR gamma) and PPAR gamma coactivator 1 alpha (PGC-1 alpha) activate mouse UCP1 gene transcription. We show here that human PGC-1 alpha induced the activation of the human UCP1 promoter by PPAR gamma. Adenovirus-mediated expression of human PGC-1 alpha increased the expression of UCP1, respiratory chain proteins, and fatty acid oxidation enzymes in human subcutaneous white adipocytes. Changes in the expression of other genes were also consistent with brown adipocyte mRNA expression profile. PGC-1 alpha increased the palmitate oxidation rate by fat cells. Human white adipocytes can therefore acquire typical features of brown fat cells. The PPAR gamma agonist rosiglitazone potentiated the effect of PGC-1 alpha on UCP1 expression and fatty acid oxidation. Hence, PGC-1 alpha is able to direct human WAT PPAR gamma toward a transcriptional program linked to energy dissipation. However, the response of typical white adipocyte targets to rosiglitazone treatment was not altered by PGC-1 alpha. UCP1 mRNA induction was shown in vivo by injection of the PGC-1 alpha adenovirus in mouse white fat. Alteration of energy balance through an increased utilization of fat in WAT may be a conceivable strategy for the treatment of obesity.
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PMID:Acquirement of brown fat cell features by human white adipocytes. 1280 71

Extracellular superoxide dismutase (SOD3), a secretory copper-containing antioxidant enzyme, plays an important role in various oxidative stress-dependent cardiovascular diseases. Although cofactor copper is required for SOD3 activity, it remains unknown whether it can regulate SOD3 transcription. We previously demonstrated that SOD3 activity requires the copper chaperone antioxidant-1 (Atox1), involved in copper delivery to SOD3 at the trans-Golgi network (TGN). Here we show that copper treatment in mouse fibroblasts significantly increases mRNA and protein levels of SOD3, but not SOD1, which is abolished in Atox1-deficient cells. Copper promotes Atox1 translocation to the nucleus. Promoter deletion analysis identifies copper- and Atox1-response elements (REs) at the SOD3 promoter. Gel-shift and ChIP assays reveal that Atox1 directly binds to the Atox1 RE in a copper-dependent manner in vitro and in vivo. Adenovirus-mediated reexpression in Atox1(-/-) cells of nucleus-targeted Atox1 (Atox1-NLS), but not TGN-targeted Atox1 (Atox1-TGN), increases SOD3 transcription without affecting SOD3 activity. Importantly, reexpression of both Atox1-NLS and Atox1-TGN together, but not either alone, in Atox1(-/-) cells increases SOD3 activity. SOD3 transcription is positively regulated by copper through the transcription factor function of Atox1, whereas the full activity of SOD3 requires both the copper chaperone and the transcription factor functions of Atox1. Thus, Atox1 is a potential therapeutic target for oxidant stress-dependent cardiovascular disease.
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PMID:Novel mechanism for regulation of extracellular SOD transcription and activity by copper: role of antioxidant-1. 1897 92

Endothelial inflammation plays a critical role in the development and progression of cardiovascular disease, albeit the mechanisms need to be fully elucidated. Nur77 is highly expressed in vascular endothelial cells (ECs) and plays a role in the regulation of cell proliferation and angiogenesis; its role in vascular inflammation, however, remains unknown. Treatment of human umbilical vein ECs (HUVECs) with tumor necrosis factor (TNF)-alpha substantially increased the transcription and protein expression of Nur77 in a dose and time-dependent manner, as determined by Northern blot and Western blot analysis. Adenovirus mediated overexpression of Nur77 markedly increased the intracellular levels of IkappaBalpha by approximately 4-fold, whereas overexpression of dominant negative Nur77 (DN-Nur77), which lacks its transactivation domain, had no effect on IkappaBalpha expression, suggesting that Nur77 is an important transcriptional factor in controlling IkappaBalpha expression in ECs. Furthermore, overexpression of Nur77 significantly increased IkappaBalpha promoter activity via directly binding to a Nur77 response element in the IkappaBalpha promoter. Importantly, overexpression of Nur77, but not DN-Nur77, protected ECs against the TNF-alpha- and interleukin-1beta-induced endothelial activation, as characterized by attenuation in the nuclear factor kappaB activation, expression of adhesion molecules ICAM-1 and VCAM-1, and monocytic adherence to ECs. These results indicate that Nur77 negatively regulates the TNF-alpha- and interleukin-1beta-induced vascular EC activation by transcriptionally upregulation of IkappaBalpha expression.
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PMID:The orphan nuclear receptor Nur77 suppresses endothelial cell activation through induction of IkappaBalpha expression. 1932 55

Angiotensin II is a major effector molecule in the development of cardiovascular disease. In vascular smooth muscle cells (VSMCs), angiotensin II promotes cellular proliferation and extracellular matrix accumulation through the upregulation of plasminogen activator inhibitor-1 (PAI-1) expression. Previously, we demonstrated that small heterodimer partner (SHP) represses PAI-1 expression in the liver through the inhibition of TGF-beta signaling pathways. Here, we investigated whether SHP inhibited angiotensin II-stimulated PAI-1 expression in VSMCs. Adenovirus-mediated overexpression of SHP (Ad- SHP) in VSMCs inhibited angiotensin II- and TGF-beta-stimulated PAI-1 expression. Ad-SHP also inhibited angiotensin II-, TGF-beta- and Smad3-stimulated PAI-1 promoter activity, and angiotensin II-stimulated AP-1 activity. The level of PAI-1 expression was significantly higher in VSMCs of SHP(-/-) mice than wild type mice. Moreover, loss of SHP increased PAI-1 mRNA expression after angiotensin II treatment. These results suggest that SHP inhibits PAI-1 expression in VSMCs through the suppression of TGF-beta/Smad3 and AP-1 activity. Thus, agents that target the induction of SHP expression in VSMCs might help prevent the development and progression of atherosclerosis.
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PMID:Orphan nuclear receptor small heterodimer partner inhibits angiotensin II- stimulated PAI-1 expression in vascular smooth muscle cells. 1988 97

Dysregulation of the renin-angiotensin II (AngII)-aldosterone system can contribute to cardiovascular disease, such that an understanding of this system is critical. Diacylglycerol-sensitive serine/threonine protein kinase D (PKD) is activated by AngII in several systems, including the human adrenocortical carcinoma cell line NCI H295R, where this enzyme enhances chronic (24h) AngII-evoked aldosterone secretion. However, the role of PKD in acute AngII-elicited aldosterone secretion has not been previously examined. In primary cultures of bovine adrenal glomerulosa cells, which secrete detectable quantities of aldosterone in response to secretagogues within minutes, PKD was activated in response to AngII, but not an elevated potassium concentration or adrenocorticotrophic hormone. This activation was time- and dose-dependent and occurred through the AT1, but not the AT2, receptor. Adenovirus-mediated overexpression of constitutively active PKD resulted in enhanced AngII-induced aldosterone secretion; whereas overexpression of a dominant-negative PKD construct decreased AngII-stimulated aldosterone secretion. Thus, we demonstrate for the first time that PKD mediates acute AngII-induced aldosterone secretion.
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PMID:Angiotensin II-activated protein kinase D mediates acute aldosterone secretion. 1996 96

Vascular remodeling is being recognized as a fundamental process during atherosclerosis and restenosis. Cumulative studies have demonstrated that extracellular matrix (ECM) degrading enzymes play a critical role during vascular remodeling. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family is a recently identified metalloproteinase family which also has capacity to degrade ECM. ADAMTS family consists of 19 members and has been linked to a variety of physiological processes including development, angiogenesis, coagulation etc. Aberrant expression or function of ADAMTS members have been implicated to many disease states such as arthritis, cancer, thrombocytopenic purpura, but barely described with regard to cardiovascular disease. This review summarizes the recent advance with respect to the role of ADAMTS-7 in vascular remodeling. We review the structure, tissue distribution, substrate, expression and regulation of ADAMTS-7, especially highlight the fine tune by ADAMTS-7 of its substrate cartilage oligomeric matrix protein (COMP) in maintaining vascular homeostasis. By use of rat carotid artery balloon injury model to mimic vascular injury in vivo, we found that ADAMTS-7 protein was accumulated preferentially in neointima and mainly localized in vascular smooth muscle cells (VSMCs). Adenovirus-elicited ADAMTS-7 overexpression greatly accelerated VSMCs migration and proliferation both in vivo and in vitro, and subsequently aggravated neointima thickening post-injury. Conversely, siRNA-mediated ADAMTS-7 knock down bona fide inhibited VSMCs migration and proliferation in cultured VSMCs and injured arteries, and ultimately ameliorated neointima area. Further studies demonstrated that ADAMTS-7 facilitated VSMCs migration through degradation of its substrate COMP. Moreover, we elucidated that COMP has the capacity to maintain the contractile phenotype of VSMCs through interacting with integrin alpha7beta1. ADAMTS-7 may therefore serve as a novel therapeutic target for atherosclerosis and postangioplasty restenosis.
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PMID:ADAMTS-7, a novel proteolytic culprit in vascular remodeling. 2071 29

Insulin promotes hepatic apolipoprotein B100 (apoB100) degradation, whereas insulin resistance is a major cause of hepatic apoB100/triglyceride overproduction in type 2 diabetes. The cellular trafficking receptor sortilin 1 (Sort1) was recently identified to transport apoB100 to the lysosome for degradation in the liver and thus regulate plasma cholesterol and triglyceride levels. Genetic variation of SORT1 was strongly associated with cardiovascular disease risk in humans. The major goal of this study is to investigate the effect and molecular mechanism of insulin regulation of Sort1. Results showed that insulin induced Sort1 protein, but not mRNA, in AML12 cells. Treatment of PI3K or AKT inhibitors decreased Sort1 protein, whereas expression of constitutively active AKT induced Sort1 protein in AML12 cells. Consistently, hepatic Sort1 was down-regulated in diabetic mice, which was partially restored after the administration of the insulin sensitizer metformin. LC-MS/MS analysis further revealed that serine phosphorylation of Sort1 protein was required for insulin induction of Sort1 in a casein kinase 2-dependent manner and that inhibition of PI3K signaling or prevention of Sort1 phosphorylation accelerated proteasome-dependent Sort1 degradation. Administration of a PI3K inhibitor to mice decreased hepatic Sort1 protein and increased plasma cholesterol and triglyceride levels. Adenovirus-mediated overexpression of Sort1 in the liver prevented PI3K inhibitor-induced Sort1 down-regulation and decreased plasma triglyceride but had no effect on plasma cholesterol in mice. This study identified Sort1 as a novel target of insulin signaling and suggests that Sort1 may play a role in altered hepatic apoB100 metabolism in insulin-resistant conditions.
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PMID:Insulin resistance induces posttranslational hepatic sortilin 1 degradation in mice. 2580 2

Epoxyeicosatrienoic acids (EETs) have beneficial effects on cardiovascular disease. Soluble epoxide hydrolase (sEH) metabolizes EETs to less active diols, thus diminishing their biological activity. sEH inhibitors can suppress the progression of atherosclerotic lesions in animal models. However, the regulation of sEH in vascular smooth muscle cells (VSMCs) and role of sEH in patients with atherosclerosis have not been evaluated. We hypothesize that sEH in VSMCs plays a pivotal role in atherosclerosis and injury-induced neointima formation. In this study, sEH expression in human autopsy atherosclerotic plaque was determined by immunohistochemistry. In cultured rat and human VSMCs, the phenotypic switching marker and sEH expression induced by platelet-derived growth factor-BB (PDGF-BB) were examined by Western blot analysis. Carotid-artery balloon injury was performed after adenovirus-mediated overexpression of sEH or oral administration of a potent sEH inhibitor in Sprague-Dawley rats. sEH was highly expressed in VSMCs of the intima and media within human atherosclerotic plaque. In vitro, PDGF-BB upregulated the expression in VSMCs after transcription and promoted cell proliferation and migration; the latter effect could be largely attenuated by an sEH inhibitor. Adenovirus-mediated overexpression of sEH could mimic the effect of PDGF-BB and induce VSMC proliferation and migration. In vivo, the sEH inhibitor led to a significant decrease in injury-induced neointima formation in a rat carotid-artery injury model. These data establish the effect of sEH expression on atherosclerotic progression and vascular remodeling after injury, thus identifying a novel integrative role for sEH in VSMC phenotypic modulation and migration. Blocking sEH activity may be a potential therapeutic approach for ameliorating vascular occlusive disease.
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PMID:Soluble epoxide hydrolase is involved in the development of atherosclerosis and arterial neointima formation by regulating smooth muscle cell migration. 2645 26

Disruption of the body clock has been recognized as a risk factor for cardiovascular disease. How the circadian pacemaker interacts with the genetic factors associated with plasma lipid traits remains poorly understood. Recent genome-wide association studies have identified an expanding list of genetic variants that influence plasma cholesterol and triglyceride levels. Here we analyzed circadian regulation of lipid-associated candidate genes in the liver and identified two distinct groups exhibiting rhythmic and non-rhythmic patterns of expression during light-dark cycles. Liver-specific inactivation of Bmal1 led to elevated plasma LDL/VLDL cholesterol levels as a consequence of the disruption of the PCSK9/LDL receptor regulatory axis. Ablation of the liver clock perturbed diurnal regulation of lipid-associated genes in the liver and markedly reduced the expression of the non-rhythmically expressed gene Trib1. Adenovirus-mediated rescue of Trib1 expression lowered plasma PCSK9 levels, increased LDL receptor protein expression, and restored plasma cholesterol homeostasis in mice lacking a functional liver clock. These results illustrate an unexpected mechanism through which the biological clock regulates cholesterol homeostasis through its regulation of non-rhythmic genes in the liver.
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PMID:The Liver Clock Controls Cholesterol Homeostasis through Trib1 Protein-mediated Regulation of PCSK9/Low Density Lipoprotein Receptor (LDLR) Axis. 2654 24


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