Clinical Application of Hepatocyte Growth Factor (HGF) to cardiovascular disease: Its molecular mechanisms and possibility of molecular therapy.

肝细胞生长因子（HGF）在心血管疾病中的临床应用：其分子机制和分子治疗的可能性。

• 批准号: 13557065
• 负责人: MORISHITA Yuichi
• 金额: $ 7.23万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557065/
• 关键词: HGF; Ischemic heart disease; Endothelial cell; Celebralinfection; Gene Therapy; Peripheral arterial disease; Angiogenesis; Apoptosis; NOGA; 血球形成; アフリカツメガエル; 内皮機能; 動脈硬化; プロスタグランディン; 遺伝子治療学; ビュルガー病

1)Molecular mechanisms of HGF in regulation of vascular endothelial cells.This study demonstrated that HGF is not only growth factor but potent protector of endothelial cells. Endothelial cell death induced by high-glucose condition was inhibited by addition of HGF through the suppression of activation of caspase 3. Also, it was suggested that inhibition of cell death was mediated by up-regulation of bcl-xL and bcl-2.2)HGF-based gene therapy for ischemic diseases.We performed clinical gene therapy for peripheral arterial disease using HGF. Intramuscular injection of naked HGF plasmid is safe, feasible and can achieve successful improvement of ischemic limbs. Further clinical studies of alternative dosing regimens of gene therapy with randomized placebo-controlled trials will be required to define the efficacy of this therapy.Also, to evaluate the effect of HGF on ischemic heart disease, we employed NOGA system and demonstrated that gene transfer of HGF into myocardium resulted in increase in myocardial blood flow and decrease in ischemic area.3)Application of HGF to treatment for cerebral infarction.We demonstrated that gene transfer of HGF into ischemic brain resulted in suppression of neuron cell death and increase in blood supply as compared to that of control. Moreover, pre-treatment by trans-gene of HGF before Hgation decreased infracted area and improved behavior, suggesting its possibility of gene therapy for cerebral infarction.

1)肝细胞生长因子对血管内皮细胞调控的分子机制研究表明，肝细胞生长因子不仅是血管内皮细胞的生长因子，而且是血管内皮细胞的保护因子。加入HGF可通过抑制caspase 3的活化来抑制高糖诱导的内皮细胞死亡。2）以HGF为基础的缺血性疾病的基因治疗。我们应用HGF对外周动脉疾病进行了临床基因治疗。肌肉注射裸肝细胞生长因子质粒安全可行，可成功改善缺血肢体。进一步的临床研究的替代剂量方案的基因治疗与随机安慰剂对照试验将需要确定这种疗法的疗效。此外，评估影响肝细胞生长因子对缺血性心脏病，我们采用NOGA系统，证明HGF基因转染心肌可增加心肌血流量，减少缺血面积。肝细胞生长因子在脑梗塞治疗中的应用我们证明，与对照组相比，肝细胞生长因子基因转移到缺血脑内导致神经元细胞死亡的抑制和血供的增加。此外，肝细胞生长因子转基因治疗脑梗死后，脑梗死面积明显缩小，行为功能明显改善，提示肝细胞生长因子转基因治疗脑梗死的可能性。

项目成果

Taniyama Y et al.: "Angiogenesis and antifibrotic action by hepatocyte growth factor in cardiomyopathy."Hypertension. Jul;401. 47-53 (2002)

Taniyama Y 等人：“心肌病中肝细胞生长因子的血管生成和抗纤维化作用。”高血压。

Taniyama Y, Morishita R, Aoki M, Nakagami H, Yamamoto K, Yamazaki K, Matsumoto K, Nakamura T, Kaneda Y, Ogihara T.: "Therapeutic anglogenesis induced by human hepatocyte growth factor gene in rat and rabbit hind limb ische models : preclinical study for t

Taniyama Y、Morishita R、Aoki M、Nakagami H、Yamamoto K、Yamazaki K、Matsumoto K、Nakamura T、Kaneda Y、Ogihara T.：“在大鼠和兔后肢缺血模型中由人肝细胞生长因子基因诱导的治疗性血管生成：

Taniyama Y. et al.: "Angiogenesis and antifibrotic action by hepatocyte growth factor in cardiomyopathy."Hypertension. July ; 40, 1. 47-53 (2002)

Taniyama Y. 等人：“心肌病中肝细胞生长因子的血管生成和抗纤维化作用。”高血压。

Koibuchi N et al.: "Essential role of HGF (hepatocyte growth factor) in blood formation in Xenopus"Blood. (In press). (2004)

Koibuchi N 等人：“HGF（肝细胞生长因子）在爪蟾血液形成中的重要作用”血液。

Morishita R., Aoki M., Yo Y., Ogihara T.: "Hepatocyte growth factor as "cardiovascular hormone" : role of HGF in the pathogenesis of cardiovascular disease"Endocrine Journal. 49. 273-284 (2002)

Morishita R.、Aoki M.、Yo Y.、Ogihara T.：“肝细胞生长因子作为“心血管激素”：HGF 在心血管疾病发病机制中的作用”内分泌杂志。