Novel molecular mechanisms for cardiotonic action, their involvement in diseases and application for treatment

强心作用的新分子机制、其与疾病的关系及其治疗应用

• 批准号: 19390211
• 负责人: ITO Masaaki
• 金额: $ 11.81万
• 依托单位: Mie University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2007
• 资助国家: 日本
• 起止时间: 2007 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-19390211/
• 关键词: 心筋ミオシン; リン酸化; ミオシン軽鎖キナーゼ; ミオシンホスファターゼ; 心不全

The regulatory mechanism, function and the involvement in pathologic conditions of cardiac myosin light chain (MLC2) phosphorylation were investigated. Cardiac MLC2 was found to be phosphorylated by cardiac myosin light chain kinase (cMLCK), but not by smooth MLCK nor ZIP-kinase. However, cMLCK was not detected in several animal species, suggesting the existence of another (iso)forms of cardiac MLCK. Biochemical characteristics of cMLCK were different from those of smMLCK including the enzyme kinetics and the sensitivity for antagonists. The overexpression of cardiac myosin phosphatase in heart induced a reduction of MLC2 phosphorylation levels concomitant with a Ca^<2+> desensitization of contraction and decreased LV contractility, resulting in LV enlargement. Thus the phosphorylation of cardiac MLC2 plays a significant role in maintaining normal cardiac function. Agonist stimulation including endothelin-1 induced the expression of cMLCK and increased the phosphorylation level of MLC2. In addition, the expression of cMLCK and the phosphorylation levels of MLC2 were varied in several animal models, suggesting the phosphorylation of MLC2 might be involved in the several pathologic conditions in heart.

探讨心肌肌球蛋白轻链（MLC 2）磷酸化的调控机制、功能及其在病理状态中的作用。心肌MLC 2被心肌肌球蛋白轻链激酶（cMLCK）磷酸化，但不被平滑肌MLCK或ZIP激酶磷酸化。然而，在几种动物种属中未检测到cMLCK，表明存在另一种（同种）形式的心脏MLCK。cMLCK的生化特性与smMLCK不同，包括酶动力学和对拮抗剂的敏感性。心肌肌球蛋白磷酸酶在心脏中的过度表达诱导MLC 2磷酸化水平降低，伴随着收缩的Ca^2+脱敏和LV收缩力降低，导致LV扩大。因此，心脏MLC 2的磷酸化在维持正常心脏功能中起着重要作用。包括内皮素-1在内的激动剂刺激诱导cMLCK的表达并增加MLC 2的磷酸化水平。此外，在几种动物模型中，cMLCK的表达和MLC 2的磷酸化水平不同，提示MLC 2的磷酸化可能参与了心脏的几种病理状态。

项目成果

Human atrial natriuretic peptide preserved infract-related myocardial blood flow quantified by perfusion MRI in patients with acute myocardial infarction

人心房钠尿肽通过灌注 MRI 定量保存急性心肌梗死患者的梗死相关心肌血流量

• 发表时间: 2009
• 作者: Kurita T.;et al.
• 通讯作者: et al.

Presence of myocardial scar is strongly associated with abnormal regional myocardial blood flow in hypertrophic cardiomyopathy

肥厚型心肌病中心肌疤痕的存在与局部心肌血流异常密切相关

• 发表时间: 2009
• 作者: Nakajima H.;et al.
• 通讯作者: et al.

Serum intact parathyroid hormone levels predict hospitalization for heart failure.

血清完整甲状旁腺激素水平可预测因心力衰竭而住院的情况。

• 发表时间: 2009
• 期刊: Heart 95
• 作者: Sugimoto T;Tanigawa T;Onishi K;Fujimoto N;Matsuda A;Nakamori S;Matsuoka K;Nakamura T;Koji T;Ito M.
• 通讯作者: Ito M.

ラット高血圧自然発症モデルに対する種々の降圧薬の効果とミオシン軽鎖リン酸レベルの変化とその機序に関する検討

各种降压药物及肌球蛋白轻链磷酸盐水平变化对大鼠自发性高血压模型的影响及其机制研究

• 发表时间: 2010
• 作者: 小西克尚;岡本隆二;藤田聡;谷口正弥;伊藤正明
• 通讯作者: 伊藤正明

Human atrial natriuretic peptide preserved infract-related myocardial blood flow quantified by perfusion MRI in patients with acute myocardial infarction.

通过灌注 MRI 对急性心肌梗死患者进行定量，人心房钠尿肽可保留与梗死相关的心肌血流。

• 发表时间: 2009
• 作者: Kurita T;Tanigawa T;Sakuma H;Sato K;Nakajima H;Nakamori S;Ichikawa Y;Kitagawa K;Matsuoka K;Onishi K;Nakamura T;Ito M
• 通讯作者: Ito M