Protein phosphatase 2A Cα subunit knockout cardiac energy metabolism due to remodeling
|School||Nanjing Normal University|
|Keywords||PP2A Cα c-Myc heart hypertrophy heart failure energy metabolism remodeling|
Reversible phosphorylation is a crucial way to regulate protein functions as post-translational modification based on kinases and phosphatases. Protein phosphatase 2A(PP2A) is such a phosphatase that is widely distributed and multi-functional which comprises three subunits including a scaffold subunit A, a regulatory subunit B, and a catalytic subunit C. With an a-MHC driven knockout of PP2A Ca to inhibit the holoenzyme activity of PP2A, the mouse demonstrated heart hypertrophy at the 8th day and died soon due to congestive heart failure around the postnatal 12th to 14th day. The unusual size and number of mitochondrion had been observed through transmission electron microscopy in our previous study.Notably, the heart remodeling in this animal model developed rapidly in only a few days, when the energy metabolism should have shifted from glycolysis to fatty acid P-oxidation at this developmental stage but would be reversed in pathological heart hypertrophy. Accoding to our study, (1) The mRNA level of some key regulator of energy metabolism declined apparently in the knockout group, including Cpt-1α, Cpt-1β, Cpt-2 and CD36 as fatty acid transporters, MCAD and Echl of fatty acidβ-oxidation; ENO1α, LDHA, and HK2 of glycolysis; and TFAM, POLG, POLG2, Ndufa2, Ndufa8, Cycs, Cox7a2, Cox4il and ATP5i related to mitochondria functions. Mitochondria transmembrane potentials also decreased consistent with the down-regulation of mitochondria genes. However, the mRNA level of the reported transcription factors in charge of the energy remodeling remained unchanged including PPARa, PGC-la and c-Myc. Interestingly,10 decreased genes listed above are targets of c-Myc which suggested that c-Myc played as the nexus in the PP2A Ca knockout induced energy remodeling. (2) Compared with other two heart hypertrophy models, Hsp27 overexpression and RHAU knockout, similar disturbance of energy metabolism was observed, which indicated the prevalence of energy metabolism in heart hypertrophy. (3) Direct physical interaction between PP2A Ca and c-Myc was verified, though no change of P-catenin (an upper-stream regulator of c-Myc) or Serine 62 phosphorylation level of c-Myc was observed. Surprisingly, we found that c-Myc in the knockout group was removed from nucleus which suggested a potential mechanism of PP2A’s regulatory role on c-Myc. (4) A lentivirus based shRNA knock down model of PP2A Ca on NRVM was established, which provided a good way to study PP2A Ca’s role in vitro. In conclusion, PP2A Ca ablation would lead to energy metabolism remodeling in the heart with down-regulated c-Myc’s target genes. Although the precise mechanism in the interaction of PP2A and c-Myc remained elusive, our data suggested that the loss of function of PP2A led to the redistribution of c-Myc hence disrupted the energy metabolism pattern in the pathological development of the heart.