Monday, October 7, 2024
10/7/2024
PROJECT SUMMARY Cardiomyopathy and heart failure are leading causes of morbidity and mortality world-wide. In addition to ventricular dysfunction, heart-failure associated ventricular arrhythmias cause sudden death with few disease-modifying therapies. Changes in myocardial conduction, increased fibrosis, alterations of ion channel characteristics and genetic susceptibilities have all been postulated to underlie the increased risk of arrhythmia in heart failure, but no unifying mechanism is known. Post- translational modifications (PTMs) of cardiac proteins have emerged as critical factors in mediating normal physiologic function or leading to heart disease when dysregulated. Recently mutations in the N-terminal acetyltransferase complex type A (NatA) have been identified in patients with congenital heart disease, cardiomyopathy, and arrhythmia. This protein complex acetylates the N-terminus of nascent proteins regulating stability, subcellular localization, and complex formation, with nearly 40% of the proteome as potential targets. We have recently identified a large family with a novel mutation in the catalytic subunit of NatA, NAA10. Male patients have severely prolonged QTs, recurrent arrhythmias, developmental delay, learning disabilities, and cardiomyopathy, with female patients more variably affected. We created models of NAA10 dysfunction using induced pluripotent stem cells (iPSCs) derived from several affected male patients. Electrophysiologic analysis of differentiated iPSC-derived cardiomyocytes (iPSC-CMs) demonstrated action potential duration (APD) prolongation, abnormalities of sarcomeric structure, calcium handling and corresponding dysregulation of sodium and potassium currents. Establishing a network of collaborators, we investigated the mechanism of NAA10 dysfunction and developed an animal model for cardiac- specific ablation of NAA10. We propose to use our scalable model systems to investigate the currently unknown role of N-terminal acetylation within the heart as an entry point to understanding the mechanisms of arrhythmia risk in heart failure. In Aim 1, we will determine the mechanism of how N-terminal acetylation regulates sodium and potassium ion channels along with the discovery of other target proteins. In Aim 2, we will use recently developed murine models to selectively ablate Naa10 and the paralogue Naa12 within the heart to determine the causative mechanisms of N-terminal acetylation in heart failure and arrhythmogenesis. In Aim 3, we examine the contribution of N-terminal acetylation in acquired forms of heart disease including human heart failure. This transformative proposal will provide novel mechanistic insight into the poorly understood role of N-terminal acetylation in cardiovascular disease with potential for improved arrhythmia risk stratification and therapeutic development.
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