Myosin Light Chain Dephosphorylation by PPP1R12C Promotes Atrial Hypocontractility and Atrial Fibrillation

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Project Summary / Abstract Thromboembolic stroke is a leading cause of death from atrial fibrillation (AF). Current strategies to prevent AF-induced stroke, such as oral anticoagulants, have significant risks and incompletely suppress stroke. Atrial contractility is significantly reduced in AF and contributes to stroke risk; however, an incomplete understanding of mechanisms regulating sarcomere function has hindered development of therapeutic approaches targeting atrial contractile dysfunction. Recent insights from our lab and others have demonstrated that hypo- phosphorylation of atrial myosin light chain (MLC2a) is a major contributor to atrial contractile dysfunction in AF. Furthermore, we have demonstrated that the protein phosphatase 1 regulatory subunit 12C (PPP1R12C) contributes to MLC2a dephosphorylation and atrial hypocontractility in AF. The long-term goal of this project is to determine the mechanisms by which protein phosphatase regulatory and catalytic subunits regulate MLC2a phosphorylation and myofilament Ca2+ sensitivity, and determine how reduced MLC2a phosphorylation contributes to atrial hypocontractility, AF susceptibility, and stroke. The objective of this application is to evaluate PPP1R12C protein expression and activity as a regulator of atrial Ca2+ sensitivity and atrial contractility in vivo. Whereas we have shown that increased PPP1R12C protein expression is associated with MLC2a dephosphorylation in human AF patients and mouse models of AF, the mechanisms regulating PPP1R12C expression remain unknown. Furthermore, the functional significance of PPP1R12C deletion or pharmacologic PPP1R12C inhibition remain untested. The central hypothesis is that there is an inverse relationship between PPP1R12C activity and atrial contractility, and that inhibition of PPP1R12C expression or activity will increase atrial contractility in AF. To test this hypothesis, three Specific Aims are proposed: Aim 1- To determine the mechanism whereby AngII signaling increases PPP1R12C expression; Aim 2- To assess whether genetic knockout of Ppp1r12c in mice increases atrial contractility; Aim 3 - To validate pharmacologic approaches to modifying PPP1R12C activity in vivo. The innovation of our project is that we are evaluating atrial hypocontractility, the only limb of Virchow's triad unaddressed for stroke prevention in AF. The proposed project would, for the first time, attempt to intervene upon the atrial contractile substrate and modify atrial cardiomyopathy in vivo. Our expected outcome from completion of the proposed Aims is an enhanced understanding of the mechanisms underlying atrial contractile dysfunction in AF, and validation of targets to increase atrial contractility and reduce stroke risk in AF.