ATGL deficiency aggravates pressure overload-triggered myocardial hypertrophic remodeling associated with the proteasome-PTEN-mTOR-autophagy pathway.

Xiao Han,Yun-Long Zhang,Qiu-Yue Lin,Hui-Hua Li,Shu-Bin Guo

doi:10.1007/s10565-022-09699-0

Abstract

Persistent myocardial hypertrophy frequently leads to heart failure (HF). Intramyocardial triacylglycerol (TAG) accumulation is closely related with cardiac remodeling and abnormal contractile function. Adipose triglyceride lipase (ATGL), a key enzyme in TAG metabolism, regulates cardiac function. However, its associated molecular pathways have not been fully defined. Here, cardiac hypertrophy and HF were induced in wild-type (WT) or ATGL knockout (KO) mice through transverse aortic constriction (TAC) for up to 4weeks. TAC in WT mice significantly reduced cardiac function and autophagy while enhancing left ventricular hypertrophy, interstitial fibrosis, inflammatory response, superoxide generation, and cardiomyocyte apoptosis, accompanied with upregulation of the proteasome activity, reduction of PTEN level and activation of AKT-mTOR signaling, and these effects were further aggravated in ATGL KO mice. Interestingly, ATGL KO-mediated cardiac dysfunction and remodeling were markedly reversed by proteasome inhibitor (epoxomicin) or autophagic activator (rapamycin), but accelerated by PTEN inhibitor (VO-OHpic) or autophagy inhibitor 3-MA. Mechanistically, ATGL KO upregulated proteasome expression and activity, which in turn mediates PTEN degradation leading to activation of AKT-mTOR signaling and inhibition of autophagy, thereby enhancing hypertrophic remodeling and HF. In conclusion, ATGL KO contributes to TAC-induced cardiac dysfunction and adverse remodeling probably associated with the proteasome-PTEN-mTOR-autophagy pathway. Therefore, modulation of this pathway may have a therapeutic effect potential for hypertrophic heart disease. TAC-induced downregulation of ATGL results in increased proteasome (β1i/β2i/β5i) activity, which in turn promotes degradation of PTEN and activation of AKT-mTOR signaling and then inhibits autophagy and ATP production, thereby leading to cardiac hypertrophic remodeling and dysfunction. Conversely, blocking proteasome activity or activating autophagy attenuates these effects.

Highlights

Sustained pressure overload frequently triggers myocardial hypertrophy and eventually resulting in heart failure (HF)
Adipose triglyceride lipase (ATGL) KO mice were subjected to transverse aortic constriction (TAC) surgery for 2 to 4 weeks to establish in vivo model of pressure overload-induced hypertrophic remodeling and dysfunction
Echocardiography revealed that relative to the sham group, TAC-treated WT mice exhibited markedly reduced of cardiac contractile functions, and that these parameters were further reduced in ATGL KO mice (Fig. 1c)

Summary

Introduction

Sustained pressure overload frequently triggers myocardial hypertrophy and eventually resulting in heart failure (HF). Cardiac hypertrophy presents with activation of fetal gene expression, protein synthesis, increased cell size, and actin reorganization (Heineke and Molkentin 2006). Several signaling pathways, including PTEN/AKT/mTOR, MAPK, and calcineurin/NFAT signaling pathways regulate cardiac hypertrophy (Heineke and Molkentin 2006). PTEN, a negative regulator of the AKT-mTOR signaling cascade, is essential in maintaining cardiac homeostasis, and its loss promotes pressure overload-induced cardiac pathological remodeling and contractile defects (Roe et al 2015; Shi et al 2020; Xu et al 2014). MTOR is a critical regulator of autophagy and cardiac hypertrophic signaling (Kim et al 2018; Li et al 2016; Shi et al 2020; Xu et al 2014). Modulation of PTEN/mTOR signaling may have therapeutic effects against cardiac hypertrophy and dysfunction

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Conclusion