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PO1-2-39

Defective Ca2+ signaling contributes to diastolic dysfunction in diabetic cardiomyopathy

[Speaker] Yoshinori Mikami:1
[Co-author] Masanori Ito:1, Shogo Hamaguchi:2, Shingo Murakami:1, Taichiro Tomida:1, Iyuki Namekata:2, Hikaru Tanaka:2, Satomi Adachi-Akahane:1
1:Department of Physiology, Faculty of Medicine, Toho University, Japan, 2:Department of Pharmacology, Faculty of Pharmaceutical Sciences, Toho University, Japan

Background: Diabetes mellitus (DM) increases the risk of heart failure due to cardiomyopathy. Left ventriclular diastolic dysfunction is one of the earliest cardiac changes in the patients of diabetic cardiomyopathy (DCM). The treatment for early stage patients may provide a better management of DCM progression. The defective Ca2+ signaling contributes to diastolic dysfunction. The aim of this study was to clarify the underlying molecular mechanism of Ca2+ signaling defects of DCM.
Methods: DM was induced in C57BL/6 mice by intraperitoneal injection of streptozotocin (STZ; 180 mg/kg body weight).
Results: In STZ-induced DM model (STZ-DM) mice, the relaxation rate of ventricular myocardium was significantly longer than those from control mice. The amplitude and basal Ca2+ concentration in the isolated ventricular myocytes from STZ-DM mice were lower and higher than those from control mice, respectively. The Ca2+ transient decay rate was slower in STZ-DM mice. The phosphorylation of phospholamban (PLN)-Ser16 accelerates Ca2+ uptake into sarcoplasmic reticulum (SR) via SR Ca2+-ATPase (SERCA). In the ventricles of mice 4 weeks after STZ injection, the levels of phosphorylation at PLN-Ser16 were significantly decreased. PLN-Ser16 is phosphorylated by PKA through βAR signaling. However, the maximal myocardial response to βAR stimulation and the expression levels of βARs were not decreased in STZ-DM mice. Since insulin signaling is abolished in STZ-DM mice, we examined effects of chronic administration of insulin by osmotic pump for 3 weeks from 1 week after STZ injection. The levels of phosphorylated PLN and the relaxation rate of the isolated ventricular myocardium were recovered to the control level in the insulin-treated STZ-DM mice. In the primary culture of neonatal ventricular myocytes, insulin increased the levels of PLN-Ser16 phosphorylation.
Conclusions: Insulin signaling plays an important role independently of autonomic regulation via βAR signaling to maintain the basal levels of PLN-Ser16 phosphorylation in the ventriclar cardiomyocytes. The reduction of PLN phosphorylation level caused by impaired insulin signaling may trigger diastolic dysfunction in the early stage of DCM.
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