Regulation of cardiac function through inter-organ communication: Novel therapeutic strategy for diabetic cardiomyopathy through NO signaling

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15032
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Toho University
• Principal Investigator: Mikami Yoshinori 東邦大学, 医学部, 助教 (80532671)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 糖尿病性心筋症 / 拡張機能障害 / 一酸化窒素 / インスリン / カルシウム / ホスホランバン / 心腎連関 / 糖尿病

Outline of Final Research Achievements

Diabetic cardiomyopathy (DMCM) is characterized by the left ventricular (LV) diastolic dysfunction in the early stage. We aimed to clarify the underlying mechanism of Ca2+ signaling defects in the early DMCM. In the diabetes mellitus model mice 4 weeks after intraperitoneal streptozotocin injection (STZ-4W), diastolic function was impaired without systolic dysfunction. In the ventricle of STZ-4W mice, the phosphorylation levels of phospholamban (p-PLN) and eNOS (p-eNOS) were significantly lower than that of control mice. The chronic insulin administration restored the ventricular p-PLN and p-eNOS levels and diastolic function in vivo. We further found that insulin/NO/PKG signaling is involved in maintaining the basal level of phosphorylated PLN. These effects were not correlated with blood glucose level. These results indicate that the reduction of p-PLN level caused by loss of insulin signaling is crucial for LV diastolic dysfunction in the early onset of DMCM.

Free Research Field

生理学・薬理学

Academic Significance and Societal Importance of the Research Achievements

本研究は、糖尿病性心筋症早期にみられる拡張機能障害の発症に、インスリンシグナル下流NO/PKG経路の不全が寄与することを見出したものである。糖尿病性心筋症の早期ステージにおけるカルシウムシグナルの制御機構破綻の分子機序を明らかにしたという学術的意義がある。同時に、早期での治療介入の重要性、および、糖尿病性心筋症の新規治療標的としてのインスリン／NO／PKGシグナル経路を示した点において社会的意義がある。