Activation of FMS ‐like tyrosine kinase 3 protects against isoprenaline‐induced cardiac hypertrophy by improving autophagy and mitochondrial dynamics

Abstract

FMS-like receptor tyrosine kinase 3 (Flt3) expression was reported to increase in the heart in response to pathological stress, but the role of Flt3 activation and its underlying mechanisms remain poorly elucidated. This study was designed to investigate the role of Flt3 activation in sympathetic hyperactivity-induced cardiac hypertrophy and its mechanisms through autophagy and mitochondrial dynamics. In vivo, cardiac hypertrophy was established by subcutaneous injection of isoprenaline (6 mg/kg•day) in C57BL/6 mice for 7 consecutive days.The Flt3-ligand intervention was launched 2 h prior to isoprenaline each day. In vitro, experiments of cardiomyocyte hypertrophy, autophagy, and mitochondrial dynamics were performed in neonatal rat cardiomyocytes (NRCMs). Our results revealed that the expression level of Flt3 protein was significantly increased in the hypertrophic myocardium provoked by isoprenaline administration. Flt3ligand intervention alleviated isoprenaline-induced cardiac oxidative stress, hypertrophy, fibrosis, and contractile dysfunction. Isoprenaline stimulation impaired autophagic flux in hypertrophic mouse hearts, supported by the accumulation of LC3II and P62 proteins, while Flt3-ligand restored the impairment of autophagic flux. Flt3 activation normalized the imbalance of mitochondrial fission and fusion in the hearts of mice evoked by isoprenaline as evidenced by the neutralization of elevated mitochondrial fission markers and reduced mitochondrial fusion markers. In NRCMs, Flt3-ligand treatment attenuated isoprenaline-stimulated hypertrophy, which was abolished by a

The Current State of Research on Sirtuin-Mediated Autophagy in Cardiovascular Diseases

“…SIRT1 activates downstream effectors of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and fibroblast growth factor 21 (FGF21) to promote autophagy [ 33 ]. Additionally, SIRT1 promotes transcription factor EB (TFEB) nuclear translocation and deacetylation, thereby activating the p53 and PI3K/AKT signaling pathways to promote autophagy and maintain mitochondrial dynamics balance [ 19 , 34 ]. During endoplasmic reticulum stress (ERS), SIRT1 expression is suppressed, and autophagy decreases.…”

“…Insufficient autophagy during heart failure is associated with impaired SIRT1/PGC-1α and AMPK signaling, as well as the activation of the Akt/mTOR pathway. The upregulation of SIRT1, PGC-1α, and AMPK, along with inhibition of the Akt/mTOR pathway, promotes autophagy, diminishes myocardial hypertrophy, and improves heart failure [ 11 , 19 ]. The treatment of cardiac cells with Ang II results in a decrease in the expression of SIRT3 and autophagy-related proteins and an increase in the mRNA levels of atrial natriuretic peptide and B-type natriuretic peptide.…”

“…Both Sirtuins and autophagy are acknowledged as crucial factors in the pursuit of prolonging lifespan and protecting organisms against age-related diseases and metabolic disorders [ 8 , 9 , 10 , 11 ]. Sirtuin-mediated autophagy is activated or suppressed under pathological conditions and plays a vital role in some cardiovascular diseases, including atherosclerosis (AS), myocardial ischemia/reperfusion (MI/R) injury, hypertension, heart failure, diabetic cardiomyopathy (DCM), drug-induced myocardial damage, and cardiogenesis/cardiac maintenance [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. Sirtuins exert their influence on autophagy by regulating the gene expression of autophagy-related proteins and their post-translational modifications, thereby affecting their activity and subcellular localization [ 10 ].…”

Flt3 Activation Mitigates Mitochondrial Fragmentation and Heart Dysfunction through Rebalanced L-OPA1 Processing by Hindering the Interaction between Acetylated p53 and PHB2 in Cardiac Remodeling

“…Activation of Flt3 induces the activation of many intermediate signal-transduction mediators, determining cell survival, proliferation, differentiation, and metabolism [ 12 ]. Recent studies from ours [ 13 , 14 ] and others [ 15 ] demonstrated a notable augmentation in the expression of Flt3 in hearts subjected to pathological stress, but its physiological functions and pathological significance remain largely unknown. Our previous studies have demonstrated that cardiac pathological stress triggers the expression of Flt3 in cardiomyocytes, and Flt3 activation with its specific ligand (FL) remarkably reversed Angiotensin II or isoprenaline (ISO)-induced cardiac hypertrophy and cardiac adverse remodeling through AMPK/mTORC1/FoxO3a or SIRT1/p53 signaling [ 13 , 14 ].…”

“…In contrast, LAD-induced cardiac remodeling involves cardiomyocyte apoptosis, necrosis, the disorder of mitochondrial morphology and function, as well as the loss in the number of cardiomyocytes [ 17 ]. Nevertheless, all of these insults elicit mitochondrial dynamics imbalance and oxidative stress while reducing the expression of SIRT1 [ 13 ]. Therefore, we conducted these two experimental models to investigate how Flt3 regulates p53-mediated L-OPA1 processing in the cardiomyocytes.…”