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Activated FMS‐like tyrosine kinase 3 ameliorates angiotensin II‐induced cardiac remodelling

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Acta Physiologica

Published online on


["\nAbstract\n\nAim\nFMS‐like receptor tyrosine kinase 3 (Flt3) has been reported to be increased in cardiomyocytes responding to ischaemic stress. This study was to determine whether Flt3 activation could ameliorate pressure overload‐induced heart hypertrophy and fibrosis, and to elucidate the mechanisms of action.\n\n\nMethods\nIn vivo cardiac hypertrophy and remodelling experiments were conducted by infusing angiotensin II (Ang II) chronically in male C57BL/6 mice. Flt3‐specific ligand (FL) was administered intraperitoneally every two days (5 µg/mouse). In vitro experiments on hypertrophy, apoptosis and autophagy mechanism were performed in neonatal rat cardiomyocytes (NRCMs) and H9c2 cells with adenovirus vector‐mediated overexpression of Flt3.\n\n\nResults\nOur results demonstrated that following chronic Ang II infusion for 4 weeks, the mice exhibited heart hypertrophy, fibrosis, apoptosis and contractile dysfunction. Meanwhile, Ang II induced autophagic responses in mouse hearts, as evidenced by increased LC3 II and decreased P62 expression. These pathological alterations in Ang II‐treated mice were significantly ameliorated by Flt3 activation with FL administration. In NRCMs and Flt3‐overexpressed H9c2 cells, FL attenuated Ang II‐induced pathological autophagy and inactivated AMPK/mTORC1/FoxO3a signalling, thereby efficiently mitigating cell hypertrophy and apoptosis. Conversely, the AMPK activator metformin or the mTORC1 inhibitor rapamycin reversed the effects of FL on the alterations of autophagy, hypertrophy and apoptosis in cardiomyocytes induced by Ang II.\n\n\nConclusion\nFlt3 activation ameliorates cardiac hypertrophy, fibrosis and contractile dysfunction in the mouse model of chronic pressure overload, most likely via suppressing AMPK/mTORC1/FoxO3a‐mediated autophagy. These results provide new evidence supporting Flt3 as a novel therapeutic target in maladaptive cardiac remodelling.\n\n", "Acta Physiologica, Volume 230, Issue 2, October 2020. "]