Isozyme-Specific Pharmacological Properties of Protein Kinase C and Approaches to New Drug Development

蛋白激酶 C 同工酶特异性药理学特性和新药开发方法

• 批准号: 15390245
• 负责人: KIHARA Yasuki
• 金额: $ 6.02万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390245/
• 关键词: Protein Kinase C; Heart Failure; Myocardial Iscjhemia; Dahl Salt-Sensitive Rats; Ventricular Remodeling; Reperfusion Injury; エンドセリン

We tested hypothesis that JTV519 protects the cardiomyocytes from ischemia/reperfusion injury by inhibiting coupling of activated/translocated PKCd with its substrate proteins. We found that JTV519 facilitates translocation of PKCd while the phosphorylation of activation sites of PKCd is inhibited. Furthermore, JTV519 binds the translocated PKCd at a hydrophobic portion of annexin V. The data suggests that annexin V is a carrier protein of the unfoled/activated PKC in the cytosolic space and JTV519 may block the release of activated PKC from this carrier protein. The data provide the new approach to regulated the key enzyme activity such as PKCd in the subcellular space.

我们验证了JTV519通过抑制激活/转位的PKCd与其底物蛋白的偶联来保护心肌细胞免受缺血/再灌注损伤的假说。我们发现JTV519促进了PKCd的易位，而抑制了PKCd激活位点的磷酸化。此外，JTV519还将转位的PKCd结合到Annexin V的疏水部分。结果表明，Annexin V是胞液间隙中未折叠/激活的PKC的载体蛋白，JTV519可能阻止该载体蛋白释放激活的PKC。这些数据为调节亚细胞空间中的关键酶活性，如PKCd提供了新的途径。

项目成果

Yuan Z, Shioji K, Kihara Y, et al.: "Cardioproteicive effects of carvedilol on acute autoimmune myocarditis : anti-inflammatory effects associated with antioxidant properties"Am.J.Physiol.. 286. H83-H90 (2004)

Yuan Z、Shioji K、Kihara Y 等人：“卡维地洛对急性自身免疫性心肌炎的心脏保护作用：与抗氧化特性相关的抗炎作用”Am.J.Physiol.. 286. H83-H90 (2004)

Noguchi T, Kihara Y, et al.: "Altered myocardial thin-filament function in the failing Dahl salt-sensitive rat heart : amelioration by endothelin block"Circulation. 107. 630-635 (2003)

Noguchi T、Kihara Y 等人：“改变衰竭的 Dahl 盐敏感性大鼠心脏的心肌细丝功能：通过内皮素阻滞改善”循环。

PKCとその心血管病態学

PKC及其心血管病理学

• 发表时间: 2004
• 期刊: BIO Clinica 19(12)
• 作者: 木原康樹;北徹
• 通讯作者: 北徹

Yoneda T, Kihara Y, et al.: "RhoA expression is not a critical determinant in hypertension evolution in salt-sensitive Dahl rats"Med.Sci.Monit.. 9. BR399-BR402 (2003)

Yoneda T、Kihara Y 等人：“RhoA 表达不是盐敏感 Dahl 大鼠高血压演变的关键决定因素”Med.Sci.Monit.. 9. BR399-BR402 (2003)

Cardioprotective effects of carvedilol on acute autoimmune myocaridtis : anti-inflammatory effects associated with antioxidant property.

卡维地洛对急性自身免疫性心肌炎的心脏保护作用：与抗氧化特性相关的抗炎作用。

• 发表时间: 2004
• 期刊: Am.J.Physiol. 286
• 作者: Yuan Z;Shioji K;Kihara Y;Takenaka H;Onozawa Y;Kishimoto C.
• 通讯作者: Kishimoto C.