Abstract 265: CITED4 Induces Physiologic Hypertrophy and Improves Cardiac Remodeling After Ischemic Injury

Abstract

Cardiac hypertrophy is an adaptive response to increased hemodynamic stresses, which can be either physiologic, as with exercise, or pathologic, as with valvular heart disease. Recent data suggest that physiologic hypertrophy secondary to exercise may be mediated by the transcription factor CEBPβ and the p300-interacting protein CITED4. We sought to investigate the cardiovascular effects of CITED4 expression in vivo. Using a cardiac-specific and inducible transgenic mouse (Tg) model, we determined the effects of CITED4 expression on cardiac parameters including heart weight, cell size, cardiac function and gene expression. Expression of CITED4 for 3 weeks induced increases in heart weight (22% in HW/TL, p < 0.01) and cardiomyocyte (CM) size (24.5% in cell area, p < 0.001) with normal systolic function and without evidence of fibrosis. Gene profiling demonstrated increased expression of cardiac troponin, a favorable αMHC/βMHC ratio and a reduction in BNP consistent with physiologic hypertrophy. Genome-wide expression profiling of neonatal rat ventricular myocytes (NRVMs) over-expressing CITED4 demonstrated the activation of a unique set of genes including BCL2, ATP12a, Efemp1, Ifi204 and Tcf19. To further examine the potential beneficial role of CITED4, we induced ischemia by transient occlusion of the left anterior descending (LAD) coronary (30 min) followed by reperfusion for 24 hours, 6 days or 4 weeks. At 24 hrs after ischemia-reperfusion injury (IRI), neither cardiac dysfunction on echo nor infarct sizes were different between CITED4 Tg and controls. However, CITED4 Tgs showed substantial recovery of cardiac function at 4 weeks (FS: CITED4 Tg 51%, Control 34%, p < 0.01) and a 3.4-fold reduction in fibrosis (p < 0.005). Analysis of possible cellular responses responsible for the functional recovery demonstrated enhanced autophagic flux with reduced accumulation of LC3II (down 71%, p<0.05) and p62 (down 54%, p<0.005). Further examination of the involved signaling pathway revealed direct activation of mTORC1 and its effectors consistent with a growth phenotype. We conclude that CITED4 expression is sufficient to induce physiologic cardiac hypertrophy and improves cardiac remodeling after ischemic injury likely through activation of mTORC1.