Long‐term effect of gene therapy for chronic ischemic myocardium using platelet‐derived endothelial cell growth factor in dogs

Li, Wei; Tanaka, Kuniyoshi; Morioka, Koichi; Takamori, Atsushi; Handa, Mitsuteru; Yamada, Narihisa; Ihaya, Akio

doi:10.1002/jgm.1156

Cited by 13 publications

(13 citation statements)

References 26 publications

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“…12,13,33 In our previous study, we demonstrated the therapeutic effects of PD-ECGF/TP gene transfer on ischemia by promoting angiogenesis and inhibiting apoptosis (summary in Fig 5). [27][28][29] Sengupta et al 33 have reported that equimolar concentrations of PD-ECGF/TP induce a similar total monolayer recovery of wounded endothelium in vitro as well as vascular endothelial growth factor, strongly suggesting the chemotaxis functional effect of PD-ECGF/TP on endothelium. Therefore, as shown in Fig 5, we speculate that in addition to the suppressive effect of PD-ECGF/TP on VSMCs, PD-ECGF/TP itself, its enzymatic substrates, or PD-ECGF/TP-derived HO-1 expression may promote endothelial cell proliferation and protect endothelial cells from injury.…”

Section: Discussionmentioning

confidence: 93%

“…15,[27][28][29] We used gene transfection of human PD-ECGF/TP into rat VSMCs to study the mechanism of inhibitory effect of PD-ECGF/TP on VSMC, and found that inhibition of VSMC proliferation was correlated with the upregulation of p27 KIP1 and HO-1. 15 We also found that adventitial gene transfer of TP/PD-ECGF in a balloon injury rat carotid artery model markedly inhibited the intimal hyperplasia.…”

Section: Discussionmentioning

confidence: 99%

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Adventitial delivery of platelet-derived endothelial cell growth factor gene prevented intimal hyperplasia of vein graft

Handa

Morioka

et al. 2008

Journal of Vascular Surgery

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Adventitial delivery of platelet-derived endothelial cell growth factor gene prevented intimal hyperplasia of vein graft

Handa

Morioka

et al. 2008

Journal of Vascular Surgery

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“…268 This experimental gene therapy also proved to have a longterm beneficial effect in the treatment of chronic ischemic myocardium. 269 As VSMC play an important role in vessel maturation during angiogenesis, and deregulated growth or motility of VSMC contributes to the pathogenesis of vascular obstructive diseases (such as ischemia), the effect of TP on VSMC migration and proliferation was investigated. TP-overexpressing VSMC migrated and proliferated more slowly than mocktransfected VSMC.…”

Section: Tp Induces the Expression And/or Secretion Of Other Angiogenmentioning

confidence: 99%

The dual role of thymidine phosphorylase in cancer development and chemotherapy

Bronckaers¹,

Gago²,

Balzarini³

et al. 2009

Medicinal Research Reviews

177

176

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Thymidine phosphorylase (TP), also known as "platelet-derived endothelial cell growth factor" (PD-ECGF), is an enzyme, which is upregulated in a wide variety of solid tumors including breast and colorectal cancers. TP promotes tumor growth and metastasis by preventing apoptosis and inducing angiogenesis. Elevated levels of TP are associated with tumor aggressiveness and poor prognosis. Therefore, TP inhibitors are synthesized in an attempt to prevent tumor angiogenesis and metastasis. TP is also indispensable for the activation of the extensively used 5-fluorouracil prodrug capecitabine, which is clinically used for the treatment of colon and breast cancer. Clinical trials that combine capecitabine with TP-inducing therapies (such as taxanes or radiotherapy) suggest that increasing TP expression is an adequate strategy to enhance the antitumoral efficacy of capecitabine. Thus, TP plays a dual role in cancer development and therapy: on the one hand, TP inhibitors can abrogate the tumorigenic and metastatic properties of TP; on the other, TP activity is necessary for the activation of several chemotherapeutic drugs. This duality illustrates the complexity of the role of TP in tumor progression and in the clinical response to fluoropyrimidine-based chemotherapy.

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“…We have found that direct injection of a plasmid vector encoding human TYMP into ischemic canine myocardium or rabbit hindlimb promotes angiogenesis in cardiac and skeletal muscle 5,9,10 and improves myocardial function and prevents hindlimb necrosis. We also found that TYMP inhibited vascular smooth muscle cell (VSMC) proliferation and migration 11–13 .…”

Section: Introductionmentioning

confidence: 98%

Thymidine Phosphorylase Participates in Platelet Signaling and Promotes Thrombosis

Gigante

Pérez‐Pérez

et al. 2014

Circulation Research

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Rationale Platelets contain abundant thymidine phosphorylase (TYMP), which is highly expressed in diseases with high risk of thrombosis, such as atherosclerosis and type II diabetes. Objective Test the hypothesis that TYMP participates in platelet signaling and promotes thrombosis. Methods and Results By using a ferric chloride (FeCl3) induced carotid artery injury thrombosis model, we found time to blood flow cessation was significantly prolonged in Tymp−/− and Tymp+/− mice compared to wild type (WT) mice. Bone marrow transplantation and platelet transfusion studies demonstrated that platelet TYMP was responsible for the antithrombotic phenomenon in the TYMP deficient mice. Collagen-, collagen-related peptide (CRP)-, adenosine diphosphate-and/or thrombin-induced platelet aggregation were significantly attenuated in Tymp+/− and Tymp−/− platelets, and in WT or human platelets pretreated with TYMP inhibitor KIN59. Tymp deficiency also significantly decreased agonist-induced P-select in expression. TYMP contains an N-terminal SH3 domain binding proline-rich motif and forms a complex with the tyrosine kinases Lyn, Fyn and Yes in platelets. TYMP-associated Lyn was inactive in resting platelets, and TYMP trapped and diminished active Lyn after collagen stimulation. Tymp/Lyn double haploinsufficiency diminished the antithrombotic phenotype of Tymp+/− mice. TYMP deletion or inhibition of TYMP with KIN59 dramatically increased PECAM-1 tyrosine phosphorylation and diminished CRP or collagen induced AKT phosphorylation. In vivo administration of KIN59 significantly inhibited FeCl3 induced carotid artery thrombosis without affecting hemostasis. Conclusion TYMP participates in multiple platelet signaling pathways and regulates platelet activation and thrombosis. Targeting TYMP might be a novel anti-platelet and anti-thrombosis therapy.

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Long‐term effect of gene therapy for chronic ischemic myocardium using platelet‐derived endothelial cell growth factor in dogs

Abstract: We conclude that gene targeting of ischemic myocardium using PD-ECGF generated long-term improvement in cardiac function by causing angiogenesis, arteriogenesis and inhibiting apoptosis, but did not induce neoplasms in the remote organs, and may be a promising therapy.

Cited by 13 publications

References 26 publications

Adventitial delivery of platelet-derived endothelial cell growth factor gene prevented intimal hyperplasia of vein graft

Adventitial delivery of platelet-derived endothelial cell growth factor gene prevented intimal hyperplasia of vein graft

The dual role of thymidine phosphorylase in cancer development and chemotherapy

Thymidine Phosphorylase Participates in Platelet Signaling and Promotes Thrombosis

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