Abstract 843: Non-oxidized Protein Kinase G 1 Alpha Antagonizes mTORC1 Signaling in a Tuberin-dependent Manner to Ameliorate Cardiac Disease

• DOI: 10.1161/res.125.suppl_1.843
• Publication Date: 2019-10-16T17:53:59Z
• Authors: Christian U Oeing; Mark J Ranek; Brittany L Dunker...; David A Kass
• Keywords: Pressure overload

Rationale: Protein kinase G 1α (PKG1α) confers anti-hypertrophic effects in hearts subjected to mechanical and neurohumoral stress. Human heart failure with a reduced ejection fraction (HFrEF) mouse pressure overloaded present increased mechanistic target of rapamycin complex 1 (mTORC1) activity, protein aggregation, oxidative stress, and, as we previously described, PKG1α disulfide dimer formation indicative oxidation. Recently demonstrated that stimulation phosphorylates tuberin (TSC2) at one specific serine, S1365, inhibit mTORC1 signaling attenuate pathological hypertrophy. Objective: To determine if the redox state impacts its ability TSC2 chronic pressure-overload model exhibiting pathologic We hypothesize non-oxidized will increase S1365 phosphorylation antagonize signaling, thereby enhancing autophagic flux clear aggregates, culminating ameliorated cardiac disease. Methods Results: Mice expressing non-oxidizable (redox-dead) (cysteine 42 CS) knock-in mutation wild type (WT) littermate controls were overload stress via transaortic constriction (TAC) or sham surgeries. Following TAC, CS mice exhibited activation leading preventing compared WT mice. TAC had decreased expression hypertrophic genes, attenuated hypertrophy (p<0.0001), improve fractional shortening (28.14%±10.82 vs. 47.42%±15.62 CS; p<0.01). Treating an inhibitor (everolimus) abrogated hyperactivation, which lead enhanced flux, hypertrophy, improved function. Crossing phospho-null resulted lifespan (p<0.05). Conclusions: Preventing oxidation attenuates enhance prevent ameliorate following overload, dependent onTSC2 phosphorylation.