Cardiomyocyte apoptosis related with mitochondrial PTP in ischemia-reperfusion injury and the development of new cardiac drug.

缺血再灌注损伤中心肌细胞凋亡与线粒体PTP相关及新型心脏药物的开发

• 批准号: 16590443
• 负责人: HOTTA Yoshihiro
• 金额: $ 2.3万
• 依托单位: Aichi Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590443/
• 关键词: Ischemia-reperfusion injury.; ^<31>P-NMR; Fluorometry.; ESR.; apoptosis; eNOS.; MPTP; NO-releasing drug.; guinea-pig Langendorff hearts; ischemia-reperfused injury; Tunel

1.The protective effects of Na^+-H^+ exchange (NHE) inhibitors SM-198110 (Cl in structure) and SM-197378 (F in structure) had beneficial effects of LVDP (about 100% vs. drug free heart 39%) from ischemia/ reperfusion injury in Langendorff hearts. In perfused fura-2 loaded mitochondria preparation, mitochondrial Ca^<2+> uptake by acidification and Ca^<2+> content changes similar to reperfusion after global ischemia were suppressed with both NHE inhibitors. SM-197378 was found to quench directly the active oxygen radical, though SM-198110 had no effect. Number of apoptotic cells after long ischemia by reperfusion was significantly smaller in SM-197378-treated than SM-198110-treated hearts, consist with the level of activity of caspase-3 (Eur.J.Pharmacol.2004).2.5HT_<2A>(Mol.Cell.Biochem.2005), 5HT_<1A> (Eur.J.Pharmacol.2006) antagonist or SSRI (Life Sciense, in preparation) was beneficial effect against ischemia/reperfusion injury with ATP contents, quenching the active oxygen radical an … More d inhibition of mitochondrial Ca^<2+> upteke by acidification or Ca^<2+> content of perfusate. These compounds also depressed apoptotic cell and the level of activity of caspase-3 in related with 5HT.3.Atractyroside (10^<-3> M), which opens mitochondrial permeability transition pore (MPTP) also caused similar increases in mitochondrial Na^+, Ca^<2+> uptake by acidification or Ca^<2+> content change. Cyclosporine A (10^<-4> M), which inhibits MPTP or many drugs (Na-Ca exchange or Na-H inhibitor) that promote good recovery of the LVDP in the Langendorff ischemia/reperfusion injury model were also suppressed, but not FK506 (10^<-4> M), which does not inhibit MPTP (Eur.J.Pharmacol.in preparation). This result may be relate with mitochondrial Na^+ or Ca^<2+> and MPTP against ischemia-reperfusion injury.4.Nicorandil, a K_<ATP>-channel opener (Ther.Res.2005), a green tea cathechin (Eur.J.Pharmacol.In press, Life Science, in preparation), or cyclic dipeptides (in beer or the distilled residue of millet brandy) like the NO donor, was beneficial effect with inhibit MPTP5.Ex-vivo ESR spectrometry could measure directly the generation of reactive oxygen species (ROS) in ischemia-reperfusion injury model of guinea-pig Langendorff heart preparation (J.Pharmacol.Sci.2005)These results suggested that ROS and NO are closely involved to the role of the induction of myocardial cell apoptosis through MPTP in post-ischemic myocardial dysfunction. Less

1.Na^+-H^+交换（NHE）抑制剂SM-198110（结构中的Cl）和SM-197378（结构中的F）对Langendorff心脏缺血/再灌注损伤的LVDP（约100% vs. 药物心脏39%）有有益作用。在灌注的fura-2负载线粒体制剂中，两种NHE抑制剂均抑制了酸化引起的线粒体Ca ^ 2+ 摄取和类似于整体缺血后再灌注的Ca ^ 2+ 含量变化。研究发现 SM-197378 可以直接猝灭活性氧自由基，但 SM-198110 没有效果。 SM-197378 处理的心脏在再灌注长时间缺血后的凋亡细胞数量明显少于 SM-198110 处理的心脏，这与 caspase-3 的活性水平一致 (Eur.J.Pharmacol.2004).2.5HT_<2A>(Mol.Cell.Biochem.2005)、5HT_<1A> (Eur.J.Pharmacol.2006) 拮抗剂或 SSRI（生命科学，准备中）对 ATP 含量的缺血/再灌注损伤具有有益作用，通过酸化或灌注液的 Ca^<2+> 含量来猝灭活性氧自由基和抑制线粒体 Ca^<2+> 上升。这些化合物还抑制细胞凋亡以及与5HT相关的caspase-3活性水平。3.打开线粒体通透性转换孔(MPTP)的白术苷(10^-3>M)也通过酸化或Ca^2+含量变化导致线粒体Na^+、Ca^2+吸收的类似增加。抑制 MPTP 的环孢菌素 A (10^-4> M) 或许多促进 Langendorff 缺血/再灌注损伤模型中 LVDP 良好恢复的药物 (Na-Ca 交换或 Na-H 抑制剂) 也受到抑制，但不抑制 MPTP (Eur.J.Pharmacol.in 制剂) 的 FK506 (10^-4> M)。这一结果可能与线粒体Na^+或Ca^2+和MPTP抗缺血再灌注损伤有关。4.尼可地尔，一种K_<ATP>通道开放剂(Ther.Res.2005)，一种绿茶儿茶素(Eur.J.Pharmacol.In press，Life Science，准备中)，或环状二肽(存在于啤酒或小米白兰地的蒸馏残渣中) 与 NO 供体一样，抑制 MPTP5 具有有益作用。体外 ESR 光谱法可以直接测量豚鼠 Langendorff 心脏制剂缺血再灌注损伤模型中活性氧 (ROS) 的产生 (J.Pharmacol.Sci.2005)。这些结果表明，ROS 和 NO 与 MPTP 诱导心肌细胞凋亡的作用密切相关。 缺血后心肌功能障碍。较少的

项目成果

単離ブタ心筋ミトコンドリアにおけるCa^<2+>過負荷に及ぼすニコランジルの影響-mitochondrial permeability transition poreとの関連-

尼可地尔对猪离体心肌线粒体Ca^2+超载的影响-与线粒体通透性转换孔的关系-

• 发表时间: 2005
• 期刊: Therapeutic Research 26
• 作者: Watanabe S;Tagawa T;Yamakawa K;Shimabkuro M;Ueda S.;脇田康志ら
• 通讯作者: 脇田康志ら

Different effects of optical isomers of the 5-HT1A receptor antagonist pyrapyridolol against postischemic guinea-pig myocardial dysfunction and apoptosis through the mitochondrial permeability transition pore.

5-HT1A受体拮抗剂吡吡啶醇光学异构体通过线粒体通透性转换孔对缺血后豚鼠心肌功能障碍和细胞凋亡的不同作用。

• 发表时间: 2006
• 期刊: European Journal of Pharmacology 534
• 作者: Ishikawa;T.;Isono;S.;Tanaka;A.;Tagaito;Y.;Nishino;T.;Lei Huang
• 通讯作者: Lei Huang

Protective effects of nicorandil against cardiac function and apoptosis in ischemia-reperfusion guinea-pig myocardial injury.

尼可地尔对缺血再灌注豚鼠心肌损伤的心功能和细胞凋亡的保护作用。

• 发表时间: 2005
• 期刊: J.Pharmacol.Sci. 97
• 作者: Watanabe S;Tagawa T;Yamakawa K;Shimabkuro M;Ueda S.;脇田康志ら;中川和子;Shimabukuro M et al.;中川和子;Lei Huang et al.
• 通讯作者: Lei Huang et al.

Nicorandil inhibits Ca^<++> overload of an isolated porcine myocardial mitochondria through mitochondrial permeability transition pore.

尼可地尔通过线粒体通透性转换孔抑制离体猪心肌线粒体的Ca 2+ 超载。

• 发表时间: 2005
• 期刊: Therapeutic Res 26
• 作者: Yasushi Wakida;Yoshihiro Hotta;Michio Yajima;Naohisa Ishikawa;Motoyuki Fukuda;Takayuki Itoh.
• 通讯作者: Takayuki Itoh.

Differences in the effects of Na^+-H^+ exchange inhibitors on cardiac function and apoptosis in guinea-pig ischemia-reperfused hearts.

Na^-H^交换抑制剂对豚鼠缺血再灌注心脏功能和细胞凋亡影响的差异。

• 发表时间: 2004
• 期刊: Eur J Pharmacol 503
• 作者: Masayuki Hiramatsu;Takashi Hoshino;Hotta Y et al.
• 通讯作者: Hotta Y et al.