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

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 4 weeks. 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. Graphical abstract 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.

MK-886 protects against cardiac ischaemia/reperfusion injury by activating proteasome-Keap1-NRF2 signalling

“…To evaluate whether proteasome activity is involved in the impact of MK-886 on keap1 degradation and cardioprotection against I/R damage, we first analysed the effect of different doses of the proteasome inhibitor Epox, which mainly covalently binds to and targets the β5 subunit, on cardiac injury in mice as previously described [ 23 , 24 ]. Neither dose (0.5 nor 1.0 mg/kg) had significant cardiotoxic effects, as measured by LDH activity ( Fig.…”

Beta1-adrenergic receptor autoantibodies contributes to atrial remodeling by PTEN-mediated repression ofcardiomyocyte autophagy and aggravation of cardiomyocyte apoptosis

“…PTEN is a potent tumour suppressor that regulates cell growth, cell proliferation, vesicle tra cking, angiogenesis, anabolism and cancer by negatively regulating the PI3K/AKT signalling pathway [32]. PTEN is closely associated with the dynamic regulation of cellular autophagy and apoptosis [13]. For example, PTEN de ciency inhibited phagosome closure and autolysosome formation, thereby aggravating apoptosis [33].…”

“…Phosphatase and tensin homologue (PTEN) is a protein and lipid phosphatase that is highly expressed in the heart [12]. PTEN plays a role in a variety of cardiovascular diseases, such as coronary heart disease and heart failure, by regulating autophagy and apoptosis [13,14]. However, whether PTEN mediates cardiomyocyte autophagy and apoptosis in β1-AAB-induced AF and the speci c mechanisms remain unclear.…”