The Mechanism Underlying Metabolic Remodeling In Protein Phosphatase 2A Catalytic Subunit Alpha(PP2Ac?) Cardiac-specific Abolished Mouse Heart

Cardiac remodeling is generally accepted as a determinant of the clinical course ofheart failure(HF).Patients with major remodeling demonstrate progressive worseningof cardiac function,slowing or reversing remodeling has become a goal of HFtherapy.Nevertheless,our understanding of how these switches occur,when theyhappen and to what extent they change is still unclear.Therefore,a betterunderstanding of these issues would be beneficial in developing metabolic therapiesto improve cardiac pumping function.There are several lines have demonstratedabnormal phosphorylation homeostasis in the failing heart,which correlates withclinical symptoms.To determine the emblematic pattern of the alternations that occurduring pathological cardiac remodeling conditions,a PP2Aca cardiac-specificablation(KO)mouse model were studied.Our results reveal the following:1)PP2A iscrucial to maintain cardiac pump sustainability.The model of PP2Aca deficiencyexhibited a hypertrophied heart during postnatal development and died at approximately 2 weeks of age.2)Prolonged AP.duration observed in KO mice,due tothe significant reduction of transient outward K+ currents Ito and intermediate increaseICa-L currents.3)In these mice,fluctuating metabolic gene expression accompaniedthe hypertrophy.A dramatic decrease in the levels of mRNA encoding fortransporters and enzymes involved in glucose utilization,which seemed to becompensated at P9 by higher expression levels of genes controlling fatty acidutilization.Increased fatty acid uptake but not mitochondrial transport was observedon a translational and integrated level.4)507 phosphor-peptides were identified viaphosphor-proteomics.The MAPKs were identified as the major factor involved inPP2A induced cardiac remodeling.5)PP2A orchestrates ERK2 on T183 and Y185 atthe early stage of HF.6)ERK2 promotes mitochondrial fission and mitophagy.