PKG oxidation at Cys42 amplifies mTORC1 activation to worsen hypertrophic heart disease. (25th November 2020)

• Record Type: Journal Article
• Authors: Oeing, C.U; Dunkerly-Eyring, B; Pieske, B; Kass, D; Ranek, M
• Is Part Of: European heart journal. Volume 41:(2020)Supplement 2
• Publication Date: 2020-11-25
• Subjects: Basic Science - Cardiac Diseases:Heart Failure; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/ehjci/ehaa946.3675
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Rationale: Protein kinase G-1a (PKG1a) phosphorylation of tuberous sclerosis complex 2 (TSC2, or tuberin) at serine 1365 (S1365) potently suppresses mTORC1 activation. This results in greater autophagy and limits pathological hypertrophy myocytes and the heart. Cardiac stress also induce oxidation of PKG1a between cysteine 42 residues in homo-monomers, which reduces cardioprotection. Objective: We tested the hypothesis that pathological mTORC1 activation is potently amplified by concomitant PKG1a C42-oxidation, and that this is countered by stimulating soluble guanylyl cyclase-1 (GC-1). Methods and results: In mice expressing only C42-redox inhibited PKG1a (PKG1aCS), pressure-overload (PO) induces markedly less mTORC1 activation, increasing autophagic flux and reducing protein aggregation, hypertrophy, and dysfunction compared to PO in PKG1aWT mice. Similar results were obtained in cardiomyocytes exposed to endothelin-1. Protection against PO in PKG1aCS mice was similar to PKG1aWT co-treated with the mTORC1-inhibitor everolimus. TSC2 S1365 phosphorylation increased more in PKG1aCS than PKG1aWT myocardium after PO. Knock-in mice with TSC2 S1365A and PKG1aCS mutations, to prevent TSC2 phosphorylation by PKG1a displayed amplified mTORC1, cardiodepression, and mortality after PO as compared to PKG1aCS. Lastly, the marked disparity between PKG1aWT and PKG1aCS PO phenotype for TSC2 S1365 phosphorylation, mTORC1 activation, and cardiac dysfunction is overcome by BAY-602770, a direct stimulator of GC-1. Conclusion: Oxidant-induced PKG1a C42 dimerization blunts its attenuation of mTORC1 activity by reducing TSC2 S1365 phosphorylation, thereby contributing to inadequate autophagy and worsened hypertrophic dysfunction. This is ameliorated by direct GC-1 stimulation. Funding Acknowledgement: Type of funding source: Public Institution(s). Main funding source(s): DFG