Metabolomic Identification of Novel Regulators of Cardiac Oxidative Stress in Heart Failure

2016 Fiscal Year Final Research Report

• Project/Area Number: 26461070
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Kobe University
• Principal Investigator: TOH RYUJI 神戸大学, 医学研究科, 特命准教授 (50379418)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 心不全 / メタボローム解析 / βヒドロキシ酪酸 / ケトン体 / 2-アミノ酪酸 / グルタチオン

Outline of Final Research Achievements

A comprehensive quantification of serum metabolites in patients with atrial septal defect revealed that circulating levels of β-hydroxybutyrate (βOHB) and 2-aminobutyric acid (2-AB) reflected hemodynamic changes. First, we demonstrated that oxidative stress can cause myocardial βOHB accumulation by downregulation of SCOT, a key enzyme of ketone body utilization. Since we found that βOHB has anti-oxidative properties, the accumulation of myocardial βOHB may serve as a compensatory response against oxidative stress. Next, we newly revealed that 2-AB modulates glutathione (GSH) homeostasis. We proved that 2-AB is a byproduct of cysteine in GSH synthetic pathway. Intriguingly, we revealed that 2-AB increased intracellular GSH levels by activating AMPK, and exert protective effects against oxidative stress in cardiomyocytes. Furthermore, oral administration of 2-AB increased both circulating and myocardial GSH levels in mouse model of heart failure.

Free Research Field

循環器内科学