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

Abstract

Aim FMS‐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. Methods In 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. Results Our 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. Conclusion Flt3 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.

Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation

“…In line with these findings, BEN has previously been shown to modulate cytokine secretion in B-cells via the p38 MAP kinase pathway [ 112 ], which is activated downstream of Flt3 [ 119 ]. Further, Flt3 activation can suppress autophagy [ 120 ], which promotes long-term cross-presentation in murine DCs [ 121 ], and increase DC lifespan [ 122 ]. This is suggestive of a potential mechanism by which BEN induces increased expression of Flt3 and pathways by which enhanced Flt3 activation may alter DC phenotype and function in the context of alloreactivity.…”

Regulatory Dendritic Cells Induced by Bendamustine Are Associated With Enhanced Flt3 Expression and Alloreactive T-Cell Death

“…However, one report found that BEN inhibits canonical STAT3 signaling ( 32 ). STAT3 is one of several known signaling molecules downstream of Flt3 providing essential signals for differentiation, survival, and proliferation ( 13 , 48 – 51 ). We hypothesized that, by inhibiting STAT3, BEN interrupts Flt3-STAT3 signaling causing a compensatory upregulation of Flt3 surface expression.…”

Pregnancy

“…In-depth knowledge of developmental mechanisms of gene regulation does not only add to our abilities to care for pregnant women and aid a healthy start into human life. Reactivation of developmental gene expression patterns may also help us to better understand, for example, remodelling processes later in life, 18,19 or recognize embryonic or foetal mechanisms of, for example, fibrosis in the adult organism, with hopeful therapeutic perspectives 20,21 Other recent results with implications for perinatal healthcare include results on thyroid hormone dysregulation, which impairs both neuronal and glial cell development. 22 Also, during early human development, the mammalian circadian system develops gradually.…”

“…In‐depth knowledge of developmental mechanisms of gene regulation does not only add to our abilities to care for pregnant women and aid a healthy start into human life. Reactivation of developmental gene expression patterns may also help us to better understand, for example, remodelling processes later in life, 18,19 or recognize embryonic or foetal mechanisms of, for example, fibrosis in the adult organism, with hopeful therapeutic perspectives 20,21 …”