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Background Transforming growth factor beta (TGF-β) critically mediates cardiac fibrosis by transforming fibroblasts to myofibroblasts in pathological conditions. Cyclin dependent kinases (CDKs), cell cycle-regulating proteins, are known to be intimately involved in cardiac fibrosis. Among CDK isoforms, CDK1 is essential for cell cycle progression and cell division. It is reported some interphase CDKs such as CDK4 or CDK6 were involved in cardiac fibrosis, however, detailed mechanisms of cardiac fibrosis through CDK1 and its interactions with TGF-β in cardiac fibrotic process haven't been elucidated. We hypothesize that CDK1 is involved in cardiac fibrotic process via TGF-β pathway and its suppression decreases TGF-β expression and transformation to myofibroblasts from fibroblasts presenting antifibrotic effect. Methods and results Isolated neonatal rat cardiac fibroblasts were treated with angiotensin II (ANG II, 1 μM, 24 h) or phosphate-buffered saline (PBS). ANG II increased CDK1 and TGF-β in cardiac fibroblasts, by 97% and 292%, respectively (p Conclusions CDK1 positively controls cardiac fibrotic process by regulating transformation to cardiac myofibroblasts from fibroblasts via TGF-β pathway. It also presents an antihypertrophic effect on ANG II stimulation. CDK1 is a potential therapeutic target of cardiac fibrosis and hypertrophy. Funding Acknowledgement Type of funding source: Other. Main funding source(s): KAKENHI

Background Cardiac hypertrophy is an independent risk factor for heart failure and cardiac death. Hexosamine biosynthesis pathway (HBP), an accessory pathways of glycolysis, is known to be involved in the attachment of O-linked N-acetylglucosamine motif (O-GlcNAcylation) to proteins, a post-translational modification. However, the role of HBP has not been determined in pathological cardiac hypertrophy. Purpose The purpose of this study to examine whether glutamine-fructose-6-phosphate amidotransferase 2 (GFAT2), a critical enzyme of HBP, mediates cardiac hypertrophy by protein O-GlcNAcylation and activating hypertrophic signaling in cardiomyocytes. Methods and results C57BL/6J mice were treated with isoproterenol (ISO: 15 mg/kg/day, 1 week) with or without 6-Diazo-5-oxo-L-norleucine (DON, an inhibitor of GFAT: 500 μg/kg/day, 1week). ISO-treated mice (ISO+vehicle) showed cardiac hypertrophy, which were attenuated in ISO and DON-treated mice (ISO+DON) (heart weight to tibial length ratio: 7.70±0.09 vs. 7.11±0.15 mg/mm, n=12, p Conclusions GFAT2, a limiting enzyme of HBP, mediates pathological cardiac hypertrophy by Akt activation probably due to its O-GlcNAcylation. GFAT2-O-GlcNAcylation-Akt pathway might be a potential novel therapeutic target for cardiac hypertrophy.

Background Invariant natural killer T (iNKT) cells orchestrate tissue inflammation via regulating various cytokine productions, especially strongly upregulating interferon (IFN)-γ. Activation of iNKT cells have been previously reported to exert protective effects against post-infarcted cardiac remodeling and cardiac ischemia/reperfusion injury. However, the role of iNKT cells has not been determined in doxorubicin (DOX)-induced cardiomyopathy. Purpose The purpose of this study was to examine whether the activation of iNKT cells by α-galactosylceramide (αGC), which specifically activates iNKT cells, could affect DOX-induced cardiomyopathy, and if so, to elucidate its downstream target. Methods C57BL/6J mice were received the intraperitoneal injection of either αGC (0.1μg/g, n=11) or vehicle (n=13). After 1 week, these mice were treated with a low dose of DOX (18mg/kg via intravenous 3 injections over 1 week), and were followed during 14 days. Results DOX mice (DOX+vehicle) showed left ventricular (LV) dysfunction and dilatation, which were significantly ameliorated in DOX mice receiving αGC (DOX+αGC) (LV fractional shortening: 27.4±4.31 vs. 31.5±4.62%, p Conclusions Activation of iNKT cells by αGC play a protective role against DOX-induced cardiac dysfunction, which was associated with enhancing expression of IFN-γ and activating Akt. Therapies designed to activate iNKT cells might be beneficial to protect the heart from DOX injury.