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.

研究了调节机制，功能和参与心脏肌球蛋白轻链（MLC2）磷酸化的病理条件。发现心脏MLC2被心脏肌球蛋白轻链激酶（CMLCK）磷酸化，但不能通过光滑的MLCK和Zip-kinase磷酸化。但是，在几种动物物种中未检测到CMLCK，这表明存在另一种（ISO）形式的心脏MLCK。 CMLCK的生化特征与SMMLCK的生化特性不同，包括酶动力学和对拮抗剂的敏感性。心脏中心脏肌球蛋白磷酸酶的过表达诱导的MLC2磷酸化水平降低了与Ca^<2+>脱敏的收缩和LV收缩力降低，从而导致LV升高。因此，心脏MLC2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了CMLCK的表达并增加了MLC2的磷酸化水平。另外，在几种动物模型中，CMLCK的表达和MLC2的磷酸化水平有所不同，这表明MLC2的磷酸化可能与心脏中的几种病理状况有关。

项目成果

Hemodynamic Characteristics of Patients with Diastolic Heart Failure and Hypertension

• DOI: 10.1291/hypres.31.1727
• 发表时间: 2008-09-01
• 期刊: HYPERTENSION RESEARCH
• 影响因子: 5.4
• 作者: Fujimoto, Naoki;Onishi, Katsuya;Ito, Masaaki
• 通讯作者: Ito, Masaaki

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.

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.

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.

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