GFAT2 mediates cardiac hypertrophy through HBP-O-GlcNAcylation-Akt pathway

Akihito Ishikita; Shouji Matsushima; Soichiro Ikeda; Kosuke Okabe; Ryohei Nishimura; Tomonori Tadokoro; Nobuyuki Enzan; Taishi Yamamoto; Masashi Sada; Yoshitomo Tsutsui; Ryo Miyake; Masataka Ikeda; Tomomi Ide; Shintaro Kinugawa; Hiroyuki Tsutsui

doi:10.1016/j.isci.2021.103517

GFAT2 mediates cardiac hypertrophy through HBP-O-GlcNAcylation-Akt pathway

iScience. 2021 Nov 26;24(12):103517. doi: 10.1016/j.isci.2021.103517. eCollection 2021 Dec 17.

Authors

Akihito Ishikita^{1

2}, Shouji Matsushima^{1

2}, Soichiro Ikeda¹, Kosuke Okabe¹, Ryohei Nishimura^{1

2}, Tomonori Tadokoro¹, Nobuyuki Enzan^{1

2}, Taishi Yamamoto^{1

2}, Masashi Sada^{1

2}, Yoshitomo Tsutsui^{1

2}, Ryo Miyake^{1

2}, Masataka Ikeda¹, Tomomi Ide³, Shintaro Kinugawa^{1

2}, Hiroyuki Tsutsui^{1

2}

Affiliations

¹ Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka 812-8582, Japan.
² Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
³ Department of Experimental and Clinical Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.

Abstract

Molecular mechanisms mediating cardiac hypertrophy by glucose metabolism are incompletely understood. Hexosamine biosynthesis pathway (HBP), an accessory pathway of glycolysis, is known to be involved in the attachment of O-linked N-acetylglucosamine motif (O-GlcNAcylation) to proteins, a post-translational modification. We here demonstrate that glutamine-fructose-6-phosphate amidotransferase 2 (GFAT2), a critical HBP enzyme, is a major isoform of GFAT in the heart and is increased in response to several hypertrophic stimuli, including isoproterenol (ISO). Knockdown of GFAT2 suppresses ISO-induced cardiomyocyte hypertrophy, accompanied by suppression of Akt O-GlcNAcylation and activation. Knockdown of GFAT2 does not affect anti-hypertrophic effect by Akt inhibition. Administration of glucosamine, a substrate of HBP, induces protein O-GlcNAcylation, Akt activation, and cardiomyocyte hypertrophy. In mice, 6-diazo-5-oxo-L-norleucine, an inhibitor of GFAT, attenuates ISO-induced protein O-GlcNAcylation, Akt activation, and cardiac hypertrophy. Our results demonstrate that GFAT2 mediates cardiomyocyte hypertrophy by HBP-O-GlcNAcylation-Akt pathway and could be a critical therapeutic target of cardiac hypertrophy.

Keywords: Cell biology; Classification Description: Cellular physiology; Molecular physiology.