Cellular and molecular pharmacological studies on disturbance of CaィイD12+ィエD1 regulatory mechanisms in cardiomyocytes in diabetes

糖尿病心肌细胞CaD12+D1调节机制紊乱的细胞和分子药理学研究

基本信息

批准号：
10670077
负责人：
HATTORI Yuichi
金额：
$ 0.32万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

The present work was carried out in order to determine whether a decrease in cardiac NaィイD2+ィエD2-CaィイD22+ィエD2 exchanger (NCX) activity observed in diabetes is caused by a reduction in NCX protein and mRNA levels and to elucidate the significance of this decrease in alterations in [CaィイD12+ィエD1]ィイD2iィエD2 homeostasis in diabetic cardiomyocytes. The NCX current was significantly reduced in ventricular myocytes freshly isolated from streptozotocin-induced diabetic rat hearts, and its current density was about 55% of age-matched controls. Diabetes resulted in a 〜30% decrease in cardiac protein and mRNA levels of NCX1, a NCX isoform which is expressed at high levels in the heart. The reduced NCX current and the decreased protein and mRNA levels of NCX 1 in diabetes were prevented by insulin therapy. Although both diastolic and peak systolic [CaィイD22+ィエD2]ィイD2iィエD2 were not different between the two groups of myocytes, increasing external CaィイD12+ィエD1 concentration to high levels greatly elev … More ated diastolic [CaィイD12+ィエD1]ィイD2iィエD2 in diabetic myocytes. Inhibition of NCX by reduction in extracellular NaィイD1+ィエD1 by 50% could produce a marked rise in diastolic [CaィイD12+ィエD1]ィイD2iィエD2 in control myocytes in response to high CaィイD12+ィエD1, as seen in diabetic myocytes. However, cyclopiazonic acid, an inhibitor of sarcoplasmic reticulum CaィイD12+ィエD1 pump ATPase, did not modify the high CaィイD12+ィエD1-induced changes in diastolic [CaィイD12+ィエD1]I in either control and diabetic myocytes. Only in papillary muscles from diabetic rats, the addition of high CaィイD12+ィエD1 caused a marked rise in resting tension signifying a partial contracture that is possibly due to an increase in diastolic [CaィイD12+ィエD1]ィイD2iィエD2.In conclusion, a diminished NCX function in diabetic myocyes shown in this study results in part from the decreased levels of cardiac NCX protein and mRNA. We suggest that this impaired NCX function may play an important role in alterations in CaィイD12+ィエD1 handling when [CaィイD12+ィエD1]ィイD2iィエD2 rises to pathological levels. Less

The present work was carried out in order to determine whether a decrease in cardiac Naii D2+Ie D2-Caii D22+Ie D2 exchanger (NCX) activity observed in diabetes is caused by a reduction in NCX protein and mRNA levels and to elucidate the significance of this decrease in alterations in [Caii D12+Ie D1]Ie D2ii D2 homeostasis in diabetic心肌细胞。从链蛋白酶诱导的糖尿病大鼠心脏分离的心室肌细胞中，NCX电流显着降低，其电流密度约为年龄匹配的对照组的55％。糖尿病导致心脏蛋白和mRNA水平NCX1（一种NCX同工型）降低约30％，在心脏中高水平表达。通过胰岛素治疗预防NCX电流降低的NCX电流以及糖尿病中NCX 1的蛋白质和mRNA水平的降低。尽管两组肌细胞之间的糖尿病患者和峰值收缩期[CAI D22+E D2] II D2I D2并没有差异，在糖尿病性肌细胞中，将外部CAI D12+E D1浓度增加到高水平的高水平……更高的舒张压[CAI D12+E D1] II D2I D2。通过抑制糖尿病高的高CAI D12+IE D1，通过将细胞外NAI D1+E D1降低50％通过将NAI D1+E D1降低50％的抑制作用可能会产生明显的舒张压[CAI D12+E D1] II D2I D2。然而，环磷酸是肌浆网的抑制剂CAI D12+IE D1泵ATPase，在对照和糖尿病性肌动物中都没有修改高CAI D12+IE D1诱导的舒张期[CAI D12+IE D1] I的变化。 Only in papillary muscles from diabetic rats, the addition of high Cai D12+Ie D1 caused a marked rise in resting tension signing a partial contracture that is likely due to an increase in diastolic [Cai D12+Ie D1] Ii D2i D2.In conclusion, a diminished NCX function in diabetic myocyes shown in this study results in part from the decreased levels of cardiac NCX protein and mRNA。我们建议，当[CAI D12+IE D1] II D2I D2上升到病理水平时，这种受损的NCX功能可能在CAI D12+IE D1处理的改变中起重要作用。较少的