Therapy for ischemic vascular diseases using soluble TNF-alpha receptor 1 gene

利用可溶性TNF-α受体1基因治疗缺血性血管疾病

• 批准号: 14570671
• 负责人: SUGANO Masahiro
• 金额: $ 1.66万
• 依托单位: Kyushu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570671/
• 关键词: myocardial infarction; TNF-alpha; soluble TNF-alpha receptor 1; angiogenesis; gene therapy; soluble TNF-alpha receptor

Apoptosis is the major independent form of cardiomyocyte cell death in acute myocardial infarction (AMI). TNF-alpha release early in the course of AMI contributes to myocardial injury and TNF-alpha induces apoptosis in cardiomyocytes. Soluble TNF-alpha receptor 1 (sTNFR1) is an extracellular domain of TNER1 and an antagonist to TNF-alpha. Treatment with sTNFR1plasmid reduced the TNF-alpha bioactivity in the myocardium and the apoptosis of cardiomyocytes. As a result, the sTNFR1 plasmid significantly reduced the area of myocardial infarction at 2 days after coronary artery ligation. In a pathological setting, TNF-alpha inhibits the proliferative response of endothelial cells through inactivation of receptors for vascular endothelial growth factor (VEGF). Growth of HUVEC trarisfected with sTNFRI vector increased significantly compared to those transfected with control vector. The TNF-alpha-induced internucleosomic fragmentation was also significantly prevented in HUVEC transfected with sTNFRI vector compared to those trarisfected with control vector. In a rat model of hindlimb ischemia, VEGF increased but activation of KDR/flk-1 was suppressed possibly by TNF-alpha, which might impair angiogenesis. Suppression of TNF-alpha with sTNFR1 plasmid upregulated KDR/flk-1 and accelerated angiogenesis.

细胞凋亡是急性心肌梗死(AMI)心肌细胞死亡的主要独立形式。急性心肌梗死早期释放的肿瘤坏死因子-α参与心肌损伤，并诱导心肌细胞凋亡。可溶性肿瘤坏死因子-α受体1(STNFR1)是肿瘤坏死因子受体1的胞外区，是肿瘤坏死因子-α的拮抗剂。STNFR1表达载体处理后，心肌组织中的肿瘤坏死因子-α活性降低，心肌细胞的凋亡率降低。结果表明，在冠状动脉结扎后2天，sTNFR1质粒显著缩小了心肌梗死面积。在病理环境中，肿瘤坏死因子-α通过使血管内皮生长因子受体失活来抑制内皮细胞的增殖反应。转染sTNFRI载体的人脐静脉内皮细胞的生长速度明显高于对照组。与对照组相比，转导sTNFRI载体的人脐静脉内皮细胞可明显防止肿瘤坏死因子-α诱导的核小体间碎裂。在大鼠后肢缺血模型中，血管内皮生长因子升高，而KDR/Flk-1的激活可能受到肿瘤坏死因子-α的抑制，这可能会损害血管生成。STNFR1抑制肿瘤坏死因子-α表达上调KDR/Flk-1，促进血管生成。

项目成果

Sugano M, Tsuchida K, Makino N.: "Nifedipine prevents apoptosis of endothelial cells induced by oxidized LDL."J. Cardiovasc Pharmacol.. 40. 146-152 (2002)

Sugano M、Tsuchida K、Makino N.：“硝苯地平可防止氧化 LDL 诱导的内皮细胞凋亡。”J。

Sugano M, Tsuchida K, Makino N.: "Effects of soluble TNF-alfa receptor 1 on apoptosis induced by oxidized LDL in endothelial cells."Molecular Cellular Biochemistry. 258. 57-63 (2004)

Sugano M、Tsuchida K、Makino N.：“可溶性 TNF-α 受体 1 对内皮细胞中氧化 LDL 诱导的细胞凋亡的影响。”分子细胞生物化学。

Sugano M, Koyanagi M, Tsuchida K, Hata T, Makino N: "In vivo gene transfer of soluble TNF-alpha receptor 1 alleviates myocardial infarction."FASEB J. 16. 1421-1422 (2002)

Sugano M、Koyanagi M、Tsuchida K、Hata T、Makino N：“可溶性 TNF-α 受体 1 的体内基因转移可减轻心肌梗塞。”FASEB J. 16. 1421-1422 (2002)

Sugano M, Tsuchida K, Tomita H, Makino N.: "Increased proliferation of endothelial cells with overexpression of soluble TNF-α receptor I gene."A therosclerosis.. 162. 77-84 (2002)

Sugano M、Tsuchida K、Tomita H、Makino N.：“可溶性 TNF-α 受体 I 基因的过度表达增加内皮细胞的增殖。”动脉粥样硬化.. 162. 77-84 (2002)

Sugano M, Tsuchida K, Makino N.: "Intramuscular gene transfer of soluble TNF-alpha receptor 1 activates vascular endotbelial growth factor receptor (KDR/flk-1) and accelerates angiogenesis in a rat model of hindlimb ischemia."Circulation.. 103. 797-802 (2

Sugano M、Tsuchida K、Makino N.：“可溶性 TNF-α 受体 1 的肌肉内基因转移可激活血管内皮生长因子受体 (KDR/flk-1)，并加速后肢缺血大鼠模型中的血管生成。”循环.. 103