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

Adenovirus-mediated ex vivo gene transfer of basic fibroblast growth factor (bFGF), a new strategy for the treatment of chronic vascular occlusive disease, was examined in a rabbit model of hind limb ischemia. The left femoral artery was completely excised to induce an ischemic state in the hind limb of male rabbits. Simultaneously, a skin section was resected from the wound, and host fibroblasts were cultured. The cultured fibroblasts were infected with adenovirus vector containing modified human bFGF cDNA with the secretory signal sequence (AxCAMAssbFGF) or LacZ cDNA (AxCALacZ). At 21 days after femoral artery excision, the gene-transduced fibroblasts were administered through the left internal iliac artery. The fibroblasts significantly accumulated in the ischemic hind limb, and the AxCAMAssbFGF-treated cells secreted bFGF for less than 14 days without elevation of systemic bFGF level. At 28 days after cell administration, calf blood pressure ratio, angiographic score, capillary density of muscle tissue and blood flow of the left internal iliac artery were determined, and animals with AxCAMAssbFGF-treated cells showed significantly greater development of collateral vessels, as compared with those with AxCALacZ-treated cells. These findings suggest that adenovirus-mediated ex vivo gene transfer of bFGF was effective for improvement of chronic limb ischemia.
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PMID:Adenovirus-mediated ex vivo gene transfer of basic fibroblast growth factor promotes collateral development in a rabbit model of hind limb ischemia. 1142 31

Emerging evidence has shown that tumor suppressor p53 expression is enhanced in response to brain ischemia/hypoxia and that p53 plays a critical role in the cell death pathway in such an acute neurological insult. However the mechanism remains unclear. Recently it was reported that Peg3/Pw1, originally identified as a paternally expressed gene, plays a pivotal role in the p53-mediated cell death pathway in mouse fibroblast cell lines. In this study, we found that Peg3/Pw1 expression is enhanced in peri-ischemic neurons in rat stroke model by in situ hybridization analysis, where p53 expression was also induced by immunohistochemical analysis. Moreover, we found that p53 was co-localized with Peg3/Pw1 in brain ischemia/hypoxia by double staining analysis. In human neuroblastoma-derived SK-N-SH cells, Peg3/Pw1 mRNA expression is enhanced remarkably at 24 h post-hypoxia, when p53 protein expression was also enhanced at high levels. Subcellular localization of Peg3/Pw1 was observed in the nucleus. Adenovirus-mediated high dose p53 overexpression induced Peg3/Pw1 mRNA expression. Overexpression of Peg3/Pw1 reduced cell viability under hypoxic conditions, whereas that of the C-terminal-deleted mutant and anti-sense Peg3/Pw1 inhibited hypoxia-induced cell death. These results suggest that Peg3/Pw1 is involved in the p53-mediated cell death pathway as a downstream effector of p53 in brain ischemia/hypoxia.
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PMID:Peg3/Pw1 is involved in p53-mediated cell death pathway in brain ischemia/hypoxia. 1167 86

Gene therapy may be a promising approach for the treatment of brain ischemia. Because older populations are susceptible to ischemic stroke, we examined the effects of aging on adenovirus-mediated gene transfer to the ischemic brain of rats. Brain ischemia was produced by photochemical occlusion of the distal middle cerebral artery of aged and adult spontaneously hypertensive rats. Ninety minutes after ischemia, an adenoviral vector encoding beta-galactosidase was injected into the contralateral (C) and ipsilateral [peri-ischemic (I-p) and ischemic core (I-c)] parietal cortices. Cerebral blood flow (CBF) was measured by laser Doppler flowmetry. Transgene expression was scored semiquantitatively as an expression score by histochemistry and also quantitatively analyzed by chemiluminescence assay. Changes in CBF after ischemia in aged rats were not significantly different from those in adult rats, although the infarct rim in the older rats tended to be closer to the midline than in the younger rats. beta-galactosidase was detected in both neurons and non-neuronal cells at C and I-p, and was primarily present in non-neuronal cells at I-c. The expression scores 1 and 4 days after ischemia in the aged rats were similar to those in the adult rats. However, the score for the I-c at 7 days after injection was significantly greater in the older rats than in the younger adult rats. beta-galactosidase activity at I-c 7 days after ischemia in the aged rats (8.0+/-1.7mU/mg protein) was significantly greater than that in the adult rats (1.3+/-0.4, p<0.01). Adenovirus-mediated gene transfer to the ischemic brain may thus be more effective in aged rats than in adult rats.
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PMID:Adenovirus-mediated gene transfer to ischemic brain is augmented in aged rats. 1267 Jun 29

Adenovirus-mediated VEGF gene delivery is being evaluated in clinical trials as a treatment for patients with vascular diseases that stem from ischemia, such as diffuse coronary artery disease and peripheral vascular disease. Although adenoviral vectors are one of the most widely utilized vectors to deliver therapeutic genes to cells, they also have a major limitation in that their inherent immunogenicity leads to the production of neutralizing antibodies that block effective repeat administration. Although this may be true of intravenous, intranasal, and other routes of administration, recent studies have indicated that it may be possible to effectively readminister adenovirus to skeletal muscle. The present study found improved efficacy after administration of AdVEGF(121.10), an E1/E3-deleted adenovirus encoding human VEGF(121) under the control of a CMV promoter in a rat hindlimb ischemia model. As expected, repeat administration of adenovirus resulted in a marked increase of circulating neutralizing antibody, yet nanogram quantities of VEGF protein were still detectable within the hindlimb skeletal muscle after a second administration of vector. The amount of VEGF protein produced after repeat administration translated into improved efficacy as evidenced by increased blood flow as measured by laser Doppler, increased vessel number upon post-mortem angiography, and an increased number of CD31-positive vessels. These findings have important implications for increasing the efficacy of adenovirus-mediated gene therapy in the treatment of peripheral vascular disease and coronary artery disease.
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PMID:Increased revascularization efficacy after administration of an adenovirus encoding VEGF(121). 1499 23

Obesity is a risk factor for the development of cardiovascular diseases that are associated with impaired angiogenesis. Adiponectin is an adipocyte-specific adipocytokine with anti-atherogenic and anti-diabetic properties, and its plasma levels are reduced in association with obesity-linked diseases. Here, we investigated whether adiponectin regulates angiogenesis in response to tissue ischemia using adiponectin knock-out (KO) mice. Angiogenic repair of ischemic hind limbs was impaired in adiponectin-KO mice compared with wild-type (WT) mice as evaluated by laser Doppler flow method and capillary density analyses. Adenovirus-mediated supplement of adiponectin accelerated angiogenic repair in both adiponectin-KO and WT mice. Intramuscular injection of an adenovirus encoding dominant-negative AMP-activated kinase diminished the improvement in limb perfusion seen in WT mice and abolished the adiponectin-induced enhancement of perfusion. These data indicate that adiponectin can function to stimulate angiogenesis in response to ischemic stress by promoting AMP-activated kinase signaling. Therefore, adiponectin may be useful in the treatment for obesity-related vascular deficiency diseases.
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PMID:Adiponectin stimulates angiogenesis in response to tissue ischemia through stimulation of amp-activated protein kinase signaling. 1512 26

Our previous study has shown that human tissue kallikrein protected against ischemia/reperfusion-induced myocardial injury. In the present study, we investigated the protective role of local kallikrein gene delivery in ischemia/reperfusion-induced cardiomyocyte apoptosis and its signaling mechanisms in promoting cardiomyocyte survival. Adenovirus carrying the human tissue kallikrein gene was delivered locally into the heart using a catheter-based technique. Expression and localization of recombinant human kallikrein in rat myocardium after gene transfer were determined immunohistochemically. Kallikrein gene delivery markedly reduced reperfusion-induced cardiomyocyte apoptosis identified by both in situ nick end-labeling and DNA fragmentation. Delivery of the kallikrein gene increased phosphorylation of Src, Akt, glycogen synthase kinase (GSK)-3beta, and Bad(Ser-136) but reduced caspase-3 activation in rat myocardium after reperfusion. The protective effect of kallikrein on apoptosis and its signaling mediators was blocked by icatibant and dominant-negative Akt, indicating a kinin B2 receptor-Akt-mediated event. Similarly, kinin or transduction of kallikrein in cultured cardiomyocytes promoted cell viability and attenuated apoptosis induced by hypoxia/reoxygenation. The effect of kallikrein on cardiomyocyte survival was blocked by dominant-negative Akt and a constitutively active mutant of GSK-3beta, but it was facilitated by constitutively active Akt, catalytically inactive GSK-3beta, lithium, and caspase-3 inhibitor. Moreover, kallikrein promoted Bad.14-3-3 complex formation and inhibited Akt-GSK-3beta-dependent activation of caspase-3, whereas caspase-3 administration caused reduction of the Bad.14-3-3 complex, indicating an interaction between Akt-GSK-caspase-3 and Akt-Bad.14-3-3 signaling pathways. In conclusion, kallikrein/kinin protects against cardiomyocyte apoptosis in vivo and in vitro via Akt-Bad.14-3-3 and Akt-GSK-3beta-caspase-3 signaling pathways.
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PMID:Kallikrein/kinin protects against myocardial apoptosis after ischemia/reperfusion via Akt-glycogen synthase kinase-3 and Akt-Bad.14-3-3 signaling pathways. 1561 Nov 41

Telomere dysfunction contributes to reduced cell viability, altered differentiation, and impaired regenerative/proliferative responses. Recent advances indicate that telomerase activity confers a pro-angiogenic phenotype to endothelial cells and their precursors. We have investigated whether telomerase contributes to tissue regeneration following hind limb ischemia and vascular endothelial growth factor 165 (VEGF(165)) treatment. VEGF delivery induced angiogenesis and increased expression of the telomerase reverse transcriptase (TERT) and telomerase activity in skeletal muscles and satellite and endothelial cells. Adenovirus-mediated transfer of wild type TERT but not of a dominant negative mutant, TERTdn, significantly induced capillary but not arteriole formation. However, when co-delivered with VEGF, TERTdn abrogated VEGF-dependent angiogenesis, arteriogenesis, and blood flow increase. This effect was paralleled by in vitro evidence that telomerase inhibition by 3'-azido-3'-deoxythymidine in VEGF-treated endothelial cells strongly reduced capillary density and promoted apoptosis in the absence of serum. Similar results were obtained with adenovirus-mediated expression of TERTdn and AKTdn, both reducing endogenous TERT activity and angiogenesis on Matrigel. Mechanistically, neo-angiogenesis in our system involved: (i) VEGF-dependent activation of telomerase through the nitric oxide pathway and (ii) telomerase-dependent activation of endothelial cell differentiation and protection from apoptosis. Furthermore, detection of TERT in activated satellite cells identified them as VEGF targets during muscle regeneration. Because TERT behaves as an angiogenic factor and a downstream effector of VEGF signaling, telomerase activity appears required for VEGF-dependent remodeling of ischemic tissue at the capillaries and arterioles level.
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PMID:Telomerase mediates vascular endothelial growth factor-dependent responsiveness in a rat model of hind limb ischemia. 1568 94

Toll-like receptor-4 (TLR4) and its signaling molecule interleukin-1 receptor-associated kinase (IRAK-1) play an important role in host defense and tissue inflammation. Intriguingly, systemic administration of lipopolysaccharide (LPS), the agonist for TLR4, confers a cardio-protective effect against ischemic injury. However, the mechanisms leading to the cardiac protection remain largely unknown. The present study was designed to investigate the role of TLR4 activation by LPS in protecting cardiomyocytes (CM) against apoptosis in an in vitro model of ischemia and to explore the downstream mechanisms leading to the protective effect. Incubation with LPS led to activation of IRAK-1 and protected CMs against serum deprivation (SD)-induced apoptosis as demonstrated by DNA laddering, histone-DNA fragment enzyme-linked immunosorbent assay, and activation of caspase-3. Phosphatidylinositol 3-kinase/Akt, extracellular signal-regulated kinase 1/2, and IkappaB kinase beta appear to contribute to the anti-apoptotic effect of LPS since the specific inhibitors, wortmannin, PD98059, and dominant negative IKKbeta transgene expression reversed the LPS effect. To assess whether LPS improves CM function, we examined intracellular Ca(2+) transients and cell shortening in single adult rat CMs. SD for 6 h dramatically inhibited Ca(2+) transients and CM contractility. LPS at 500 ng/ml significantly improved the [Ca(2+)](i) transients and enhanced contractility in control CMs as well as in CMs subjected to SD. Importantly, transient ischemia led to rapid activation of IRAK-1 in cultured CMs and in adult rat myocardium. Adenovirus-mediated transgene expression of IRAK-1 but not its kinase-deficient mutant IRAK-1(K239S) protected CMs against SD-induced apoptosis. Taken together, these data suggest an important role of TLR4 signaling via IRAK-1 in protecting against SD-induced apoptosis.
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PMID:Lipopolysaccharide improves cardiomyocyte survival and function after serum deprivation. 1579 10

Adenovirus-mediated overexpression of endothelial nitric oxide synthase (eNOS) induces collateral artery development and substantially increases blood flow after induction of experimental acute hindlimb ischemia. However, the optimal technique of gene delivery for this or any other form of gene therapy in limb ischemia is still unknown. The purpose of this study was to determine the effect of the two most commonly used techniques, intra-arterial and intramuscular injection, on blood flow recovery, collateral artery development, and preservation of muscle mass. We compared intra-arterial injection under vascular isolation, intra-arterial injection under transient vascular occlusion, and intramuscular injection of phosphate buffered saline (PBS) or adenovirus encoding either the eNOS (AdeNOS) or LacZ (AdlacZ) gene after induction of acute hindlimb ischemia. Delivery of AdeNOS by both intra-arterial injection techniques increased eNOS activity (22.30 versus 10.56, P<0.01), blood flow (0.90+/-0.02 versus 0.69+/-0.07, P<0.001) and collateral artery development (17.56484 versus 13.74259, P<0.05) more than by intramuscular delivery. Intra-arterial injection under transient vascular occlusion led to better preservation of muscle mass, muscle architecture, and clinical ischemic index, but led to greater transgene expression in distant organs and contralateral limb muscles. Intra-arterial injection of AdeNOS under transient vascular occlusion is the optimal technique to reverse severe hindlimb ischemia in the rat. This is the first systematic comparison of different delivery techniques used in gene therapy of experimental hindlimb ischemia.
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PMID:Optimization of adenovirus-mediated endothelial nitric oxide synthase delivery in rat hindlimb ischemia. 1610 65

Advances in understanding the relationship between protein structure and DNA binding specificity have made it possible to engineer zinc finger protein (ZFP) transcription factors to specifically activate or repress virtually any gene. To evaluate the potential clinical utility of this approach for peripheral vascular disease, we investigated the ability of an engineered vascular endothelial growth factor (VEGFa)-activating ZFP (MVZ+426b) to induce angiogenesis and rescue hindlimb ischemia in a murine model. Hindlimb ischemia was surgically induced in advanced-age C57/BL6 mice. Adenovirus (Ad) encoding either MVZ+426b or the fluorescent marker dsRed was delivered to the adducter muscle of the ischemic hindlimb, and the effects on blood flow, limb salvage, and vascularization were assessed. Ad-MVZ+426b induced expression of VEGFa at the mRNA and protein levels and stimulated a significant increase in vessel counts in the ischemic limb. This was accompanied by significantly increased blood flow and limb salvage as measured serially for 4 wk. These data demonstrate that activation of the endogenous VEGFa gene by an engineered ZFP can induce angiogenesis in a clinically relevant model and further document the feasibility of designing ZFPs to therapeutically regulate gene expression in vivo.
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PMID:An engineered VEGF-activating zinc finger protein transcription factor improves blood flow and limb salvage in advanced-age mice. 1642 74


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