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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670077/
• 关键词: Diabetes; Cardiomyocyte; NaィイD1+ィエD1-CaィイD12+ィエD1 exhange; [CaィイD12+ィエD1]ィイD2iィエD2; NCX1 protein; NCX1 mRNA; NCX1 mRNA

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

本研究旨在确定糖尿病患者心脏Na + D2 + Ca + D2-Ca + D22+ NCX交换器（NCX）活性的降低是否是由NCX蛋白和mRNA水平的降低引起的，并阐明这种降低在糖尿病心肌细胞[Ca + D12+ Ca + D1] NCX D2和NCX D2稳态改变中的意义。从链脲佐菌素诱导的糖尿病大鼠心脏新鲜分离的心室肌细胞的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质和NCX 1 mRNA水平下降约30%，NCX 1是一种在心脏中高水平表达的NCX同种型。胰岛素治疗可预防糖尿病时NCX电流的降低以及NCX 1蛋白和mRNA水平的降低。虽然两组心肌细胞的舒张期和收缩期峰值[Ca ~（2+）D_2] Ca ~（2+）D_1浓度无差异，但增加细胞外Ca ~（2+）D_1浓度至高水平，可显著增加心肌细胞的收缩期和舒张期峰值[Ca ~（2+）D_2] Ca ~（2+）D_1浓度。 ...更多信息 糖尿病心肌细胞舒张期[Ca ~（2+）D_（12）+Ca ~（2+）D_（1+）D_（2+）D_（2+））] i。通过将细胞外Na + D1+ Na + D1减少50%来抑制NCX，可以使对照心肌细胞中的舒张期[Ca + D12+ Na + D1] Na + D2和Na + D2显著升高，以响应高Ca + D12+ Na + D1，如在糖尿病心肌细胞中所见。然而，cyclopiazonic酸，肌浆网Ca ~（2+）D_1泵ATP酶的抑制剂，并没有改变高Ca ~（2+）D_1诱导的舒张期[Ca ~（2+）D_1]I的变化，无论是在控制和糖尿病心肌细胞。仅在糖尿病大鼠乳头肌中，高Ca ~（2+）D_12 + Ca ~（2+）D_1引起静息张力显著升高，提示部分收缩可能是由于舒张期[Ca ~（2+）D_12 + Ca ~（2+）D_1] Ca ~（2+）D_2 + Ca ~（2+）D_1增加所致。我们认为，这种受损的NCX功能可能在[Ca ~（2+）D_12 + Ca ~（2+）D_1] Ca ~（2+）D_2i Ca ~（2+）D_2升高到病理水平时，在Ca ~（2+）D_12 + Ca ~（2+）D_1处理的改变中起重要作用。少

项目成果

服部 裕一ほか: "細胞内Ca^<2+>調節機構および情報伝達系からみた糖尿病心の異常"Therapeutic Research. 21(3)(印刷中). (2000)

Yuichi Hattori 等：“从细胞内Ca^2+调节机制和信息转导系统的角度观察糖尿病心脏的异常”治疗研究21(3)(出版中)。

Hattori Y, Matsuda M, Gando S: "Abnormalities of intracellular CaィイD12+ィエD1 regulatory mechanisms and beta-adrenoceptor signaling pathways in diabetic hearts"Therapeutic Research. 21(3) (in press). (2000)

Hattori Y、Matsuda M、Gando S：“糖尿病心脏中细胞内 CaD12+D1 调节机制和 β-肾上腺素受体信号通路的异常”治疗研究 21(3)（出版中）。