Abstract 422: CITED4 is Sufficient to Induce Physiologic Cardiac Hypertrophy and Necessary to Protect Against Pathological Hemodynamic Stress

Abstract

Cardiac hypertrophy is an adaptive response to increased physiologic or pathologic hemodynamic stress. Previous work from our laboratory suggested that the CEBPβ/ CITED4 pathway plays an important role in exercise-induced cardiac hypertrophy. Consistent with this model, our laboratory recently found that inducible cardiac expression of CITED4 in adult mice increases heart weight and cardiomyocyte size with normal systolic function and a gene expression profile consistent with physiologic growth. After ischemia-reperfusion injury (IRI), induced CITED4 mice show significant functional recovery and evidence for decreased adverse remodeling. Next, we sought to investigate the role of CITED4 in the setting of physiologic (forced swimming exercise) and pathological (transverse aortic constriction, TAC) cardiac hypertrophy. Cardiomyocyte-specific CITED4 knockout mice (C4KO) undergoing a three week swimming exercise protocol showed modestly but significantly reduced systolic function when compared to control animals (%FS controls 55.4±1.09 vs. C4KO 51.75±0.86; p=0.025). C4KO mice exposed to TAC demonstrated a more rapid and severe decline in cardiac function after TAC (at 6 weeks post surgery, %FS controls 41.55±2.06 vs. C4KO 32.51±2.67; p=0.024). Both in vitro and in vivo we demonstrate that CITED4 is necessary and sufficient for activation of mTOR signaling. Of note, mTORC1 inhibition by rapamycin abrogated the beneficial effects of CITED4 expression after IRI. Taken together, our data identify CITED4 as a novel regulator of mTOR signaling. Moreover they demonstrate that CITED4 is sufficient for physiologic growth and to protect against adverse remodeling after ischemic injury. CITED4 is also necessary for adaptive responses to pathological biomechanical stress and may represent a novel therapeutic target to mitigate adverse ventricular remodeling.