Development of Molecular Biologic Diagnostic and Therapeutic Method of Asymptomatic Myocardial Ischemia and Unstable Angina

无症状心肌缺血及不稳定型心绞痛分子生物学诊断及治疗方法的进展

• 批准号: 07557231
• 负责人: SEKO Yoshinori
• 金额: $ 1.92万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07557231/
• 关键词: myocardial ischemia; reperfusion; angina pectoris; intracellular signal transduction; VEGF; acute myocardial infarction; anti-cell-adhesion molecule therapy; 無症候性心筋虚血; 不安定狭心症; 細胞内シグナル伝達; レドックス; VFGF; 再灌流障害; 酸化ストレス; 虚血再灌流; 好中球; 接着分子

1. Molecular mechanism of cardiac adaptation to hypoxia/re oxygenation : We showed that hypoxia/re oxygenation activated Src family tyrosine kinases, p2l^<TAS>, three MAPK family member kinases and their upstream as well as downstream kinases, Jak/STAT tyro sine kinases, and a transcription factor ATF-2. The signal transduction cascades activated by these stimuli were at least partly different. 2. Autocrine mechanism via certain humoral factors involved in the activation of intracellular signaling induced by hypoxia/re oxygenation : (A) We showed that the activation of intracellular signaling in cardiac myocytes induced by hypoxia was mediated by VEGF in an auto crine fashion. (B) We found that similar autocrine mechanism was involved in the activation of intracellular signaling in cardiac myocytes induced by reoxygenation, and we are now isolating and purifying the humoral factor. 3. Sensitive detection of hypoxia/re oxygenation in the heart of patients with angina pectoris and acute myocardial infarction : (A) By measuring the serum levels of VEGF in patients with acute myocardial infarction undergoing early reperfusion therapy, we demonstrated that VEGF could be a sensitive indicator of ischemic (hypoxic) state. This also strongly supported the data of 2. (A). (B) We are now isolating and purifying the humoral factor involved in the activation of intracellular signaling induced by reoxygenation, and we suppose that the serum levels of the humaral factor will be a good indicator of reperfused (reoxygenated) state in the heart of these patients. 4. Anti-cell-adhesion molecule therapy against myocardial ischemia/reperfusion injury : We demonstrated using a rat model that in vivo administration of selectin oligopeptide or anti-sialy-Lewis^x mAb significantly reduced myocardial ischemia/reperfusion injury.

1. 心脏适应缺氧/再氧合的分子机制：我们发现缺氧/再氧合激活了Src家族酪氨酸激酶，p2l^<TAS>，三个MAPK家族成员激酶及其上游和下游激酶，Jak/STAT酪氨酸激酶和转录因子ATF-2。这些刺激激活的信号转导级联至少部分不同。2. 通过某些体液因子参与缺氧/再氧合诱导的细胞内信号激活的自分泌机制：(A)我们发现缺氧诱导的心肌细胞内信号激活是由VEGF以自动犯罪的方式介导的。(B)我们发现类似的自分泌机制参与了再氧化诱导的心肌细胞胞内信号的激活，我们现在正在分离和纯化体液因子。3. 心绞痛合并急性心肌梗死患者心脏缺氧/再氧合的敏感检测：(A)通过检测早期再灌注治疗的急性心肌梗死患者的血清VEGF水平，我们证明VEGF可以作为缺血（缺氧）状态的敏感指标。这也有力地支持了2。(A) (B)我们现在正在分离和纯化参与再氧化诱导的细胞内信号激活的体液因子，我们认为血清中体液因子的水平将是这些患者心脏再灌注（再氧化）状态的良好指标。4. 抗细胞粘附分子治疗心肌缺血/再灌注损伤：我们使用大鼠模型证明，在体内给药选择素寡肽或抗sial - lewis ^x mAb可显著减少心肌缺血/再灌注损伤。

项目成果

Seko Y,Tobe K,Takahashi N,Kaburagi Y,Kadowaki T,Yazaki Y: "Hypoxia and hypoxia/reoxygenation activate src family tyrosine kinases and p21^<ras> in cultured rat cardiac myocytes." Biochem Biophys Res Commun. 226. 530-535 (1996)

Seko Y、Tobe K、Takahashi N、Kaburagi Y、Kadowaki T、Yazaki Y：“缺氧和缺氧/复氧激活培养的大鼠心肌细胞中的 src 家族酪氨酸激酶和 p21^<ras>。”

Seko Y,Tobe K,Ueki K,Kadowaki T,Yazaki Y: "Hypoxia and hypoxia/reoxygenation activate Raf-1, mitogen-activated protein (MAP) kinase kinase, MAP kinases, and S6 kinase in cultured rat cardiac myocytes." Circ Res. 78. 82-90 (1996)

Seko Y、Tobe K、Ueki K、Kadowaki T、Yazaki Y：“缺氧和缺氧/复氧会激活培养的大鼠心肌细胞中的 Raf-1、丝裂原激活蛋白 (MAP) 激酶激酶、MAP 激酶和 S6 激酶。”

Seko Y,Enokawa Y,Tamatani T,Kannagi R,Yagita H,Okumura K,Yazaki Y: "Expression of sialyl Lewis^x in rat heart with ischemia/reperfusion and reduction of myocardial reperfusion injury by a monoclonal antibody against sialyl Lewis^x." J Pathol. 180. 305-310

Seko Y、Enokawa Y、Tamatani T、Kannagi R、Yagita H、Okumura K、Yazaki Y：“唾液酸 Lewis^x 在缺血/再灌注大鼠心脏中的表达，并通过针对唾液酸 Lewis^x 的单克隆抗体减少心肌再灌注损伤

Seko, Y.,et al.: "Restricted Usage of T-cell receptor Vα-Vβ genes in infiltrating cells in the hearts of patients with acute myocarditis……" J. Clin. Invest.96. 1035-1041 (1995)

Seko, Y. 等人：“急性心肌炎患者心脏浸润细胞中 T 细胞受体 Vα-Vβ 基因的限制使用……”J. Clin. 1035-1041 (1995)。

Seko, Y., et al.: "Perforin-positive leukemic cell infiltration in the heart of a patient with T-cell prolymphocytic leukemia." Intern. Med.34. 782-784 (1995)

Seko, Y. 等人：“T 细胞幼淋巴细胞白血病患者心脏中穿孔素阳性白血病细胞浸润。”