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

PPP1R12C 的肌球蛋白轻链去磷酸化促进心房收缩力和心房颤动

基本信息

批准号：
10617642
负责人：
Mark D McCauley
金额：
$ 63.49万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617642
关键词：
Address Angiotensin II Angiotensin Receptor Anticoagulants Arrhythmia Atrial Fibrillation Attenuated Binding Biological Assay Blood Breeding Cardiac Cardiomyopathies Catalytic Domain Cause of Death Chronic Data Endothelium Event Exclusion Functional disorder Genetic Genetic Transcription Goals Heart Heart Atrium Heart Diseases Holoenzymes Human In Vitro Intervention Knock-out Knockout Mice Knowledge Limb structure Measures Methods Microfilaments Mus Mutant Strains Mice Myocardium Myosin ATPase Myosin Light Chains Oral Osmosis Outcome Pathologic Patients Peptides Pharmaceutical Preparations Phosphorylation Play Population Predisposition Prophylactic treatment Protein Dephosphorylation Protein Inhibition Protein Overexpression Protein phosphatase Proteins Pump Reporter Genes Risk Role Saline Sarcomeres Signal Transduction Stroke Stroke prevention Structural Protein Testing Therapeutic Thrombophilia Thrombosis Time Validation auricular appendage cardiac magnetic resonance imaging in vivo inhibitor innovation insight mouse model overexpression pharmacologic prevent prophylactic protein expression stroke risk therapeutic development thromboembolic stroke transcription factor valsartan

项目摘要

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.

项目摘要/摘要