2-Aminobutyric acid modulates glutathione homeostasis in the myocardium.
A previous report showed that the consumption of glutathione through oxidative stress activates the glutathione synthetic pathway, which is accompanied by production of ophthalmic acid from 2-aminobutyric acid (2-AB). We conducted a comprehensive quantification of serum metabolites using gas chromatography-mass spectrometry in patients with atrial septal defect to find clues for understanding myocardial metabolic regulation, and demonstrated that circulating 2-AB levels reflect hemodynamic changes. However, the metabolism and pathophysiological role of 2-AB remains unclear. We revealed that 2-AB is generated by an amino group transfer reaction to 2-oxobutyric acid, a byproduct of cysteine biosynthesis from cystathionine. Because cysteine is a rate-limiting substrate for glutathione synthesis, we hypothesized that 2-AB reflects glutathione compensation against oxidative stress. A murine cardiomyopathy model induced by doxorubicin supported our hypothesis, i.e., increased reactive oxygen species are accompanied by 2-AB accumulation and compensatory maintenance of myocardial glutathione levels. Intriguingly, we also found that 2-AB increases intracellular glutathione levels by activating AMPK and exerts protective effects against oxidative stress. Finally, we demonstrated that oral administration of 2-AB efficiently raises both circulating and myocardial glutathione levels and protects against doxorubicin-induced cardiomyopathy in mice. This is the first study to demonstrate that 2-AB modulates glutathione homeostasis in the myocardium.
Division of Evidence-Based Laboratory Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan.|The Integrated Center for Mass Spectrometry, Laboratory Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan.
Yasuhiro
Y
Irino
Division of Evidence-Based Laboratory Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan.
Ryuji
R
Toh
Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan.
Manabu
M
Nagao
Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan.
Takeshige
T
Mori
Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan.
Tomoyuki
T
Honjo
The Integrated Center for Mass Spectrometry, Laboratory Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan.|Division of Epidemiology, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan.
Masakazu
M
Shinohara
Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan.
Shigeyasu
S
Tsuda
Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan.
Hideto
H
Nakajima
Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan.
Seimi
S
Satomi-Kobayashi
Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan.
Toshiro
T
Shinke
Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan.
Hidekazu
H
Tanaka
Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan.
Tatsuro
T
Ishida
Medicinal Chemistry Laboratory, Kobe Pharmaceutical University, 4-19-1, Motoyamakita, Higashinada, Kobe, 658-8558, Japan.
Okiko
O
Miyata
Division of Evidence-Based Laboratory Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan.|Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunokicho, Chuo-ku, Kobe, 650-0017, Japan.
Ken-Ichi
KI
Hirata
D000613:Aminobutyrates / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D006344:Heart Septal Defects, Atrial / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology
D000613:Aminobutyrates; C012223:alpha-aminobutyric acid; D005978:Glutathione