Role of PARP16 in Cardiac Remodeling

Abstract

Role of PARP16 in cardiac remodeling Cardiac remodeling, a complex process involving alterations in myocardial structure and function, is a major contributor to heart failure. While physiological remodeling supports cardiac function through adaptive molecular mechanisms, pathological remodeling, induced by chronic stress or disease, leads to maladaptive outcomes. A critical mechanism underlying cardiomyocyte adaptability is post-translational modification (PTM) of proteins, particularly via NAD⁺-dependent enzymes such as Poly(ADP-ribose) polymerases (PARPs). Among these, PARP16, a mono(ADP-ribosyl)transferase localized to the endoplasmic reticulum (ER), is posited to regulate stress-responsive signaling. Structurally, PARP16 possesses a catalytic domain, a transmembrane domain, and a unique His-Tyr-Tyr (HYY) active site motif, facilitating ADP-ribosylation of specific amino acid residues. Although prior research has focused on PARP16's role in ER homeostasis and the unfolded protein response (UPR), our study investigates its function in cardiac remodeling independently of the UPR. We aim to elucidate novel mechanisms by which PARP16 regulates cellular responses driving structural and functional changes in the heart, thereby contributing to a deeper understanding of cardiac pathophysiology.

Elucidate the Role of PARP16 in the Pathogenesis of Heart Failure: Cardiomyopathy, a heterogeneous group of myocardial disorders characterized by structural and functional abnormalities, culminates in progressive heart failure. Cardiac hypertrophy and dilated cardiomyopathy (DCM) represent common subtypes, often driven by sustained activation of the Ca²⁺-Calcineurin-NFAT signaling pathway. Elevated cytosolic calcium activates calcineurin, which dephosphorylates NFAT, promoting its nuclear translocation and transcription of pro-myopathy genes, thereby contributing to maladaptive remodeling and heart failure. To determine PARP16's role in heart failure, we utilized various models, including whole-body and cardiomyocyte-specific PARP16 knockout and Knock-in mice and cultured primary cardiomyocytes. Our data suggest that PARP16 has a protective role in pathological cardiomyopathy by interacting with and inhibiting NFATc2, a critical transcription factor in pathological cardiac hypertrophy signaling. These results delineate a previously uncharacterized role for PARP16 in modulating calcium-dependent signaling and ER stress responses during cardiac remodeling, suggesting its potential as a therapeutic target for heart failure. Investigate the Role of PARP16 in Regulating Lysosomal Activity in Heart: Cardiac stress response involves a biphasic process—an initial adaptive compensatory phase followed by a maladaptive decompensatory phase—which critically alters protein homeostasis in cardiomyocytes. Autophagy, a key mechanism for maintaining proteostasis through lysosomal degradation, is dynamically regulated during these phases. While initially protective, sustained stress leads to dysregulated autophagy and contributes to cardiac dysfunction. In this study, using genetically engineered mouse models—including whole-body and cardiomyocyte-specific PARP16 knockout—we demonstrate that PARP16 directly interacts with and inhibits TFEB, a master regulator of lysosomal biogenesis and autophagy. Our findings uncover a novel role for PARP16 as a negative regulator of lysosomal activity in the heart, suggesting that targeting PARP16 may offer therapeutic potential to preserve cardiac function under stress and prevent progression to heart failure.