Abstract Wed023: Ufmylation induces adaptive cardiac hypertrophy and protects against beta-adrenergic signaling-induced heart failure

Ufmylation is a novel protein modification by which protein substrates are covalently modified by the ubiquitin-like protein, UFM1 (ubiquitin-fold modifier 1), in an enzymatic cascade that includes highly conserved E1 (UBA5), E2 (UFC1) and E3 (UFL1) enzymes. Through its ability to regulate the function of cellular proteins, ufmylation controls multiple cellular and pathophysiological events and is implicated in various human diseases. We recently reported that ufmylation is dysregulated by cardiomyopathy in both human and mouse diseased hearts. Inhibition of ufmylation by targeting the E3 ligase, UFL1, in the heart (UFL1 CKO ) evokes endoplasmic reticulum (ER) stress, leading to dilated cardiomyopathy and heart failure under physiological development and hemodynamic stress included by transverse aortic constriction (TAC), demonstrating a critical role for ufmylation in maintaining ER and cardiac homeostasis. TAC surgery created sudden pressure overload, giving the heart little time to adapt; in this study, we tested the role of ufmylation in another widely used cardiac hypertrophy model: sustained adrenergic stimulation through isoproterenol (ISO) administration. Temporal echocardiography demonstrated that UFL1 CKO mice failed to develop compensatory hypertrophy, but significant reduction of cardiac function and chamber dilation. Further analysis identified isoproterenol induced maladaptive hypertrophy, increased fibrosis, and cell death in the UFL1 CKO heart. Mechanistically, adrenergic receptor signaling activation induces ufmylation, while UFL1 CKO disrupted ISO-induced adaptive transcriptomic reprogramming. This further supports the protective role of ufmylation in heart failure since the hallmark characteristic of heart failure is the activation of the sympathetic nervous system which leads to sustained β-adrenergic receptors activation.