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

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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