Abstract 13218: CITED4 is Required for Exercise-Induced Cardiac Growth and Cardiomyogenesis in Mice

Abstract

Introduction: CITED4 (CBP/p300-interacting transactivators with E [glutamic acid]/D [aspartic acid]-rich-carboxylterminal domain 4) is a transcriptional regulator which limits pathologic remodeling after ischemic and pressure overload models of cardiac stress. It is also upregulated in the heart with exercise, an effective intervention which induces physiological hypertrophy and cardiomyogenesis in adult mice. We hypothesized that CITED4 is required for exercise-induced cardiac growth and cardiomyogenesis. Methods and Results: Eight- to ten-week-old mice with cardiomyocyte-specific CITED4 knockout (C4KO) and littermate controls underwent 8 weeks of voluntary wheel running in comparison to sedentary controls. 5-Ethynyl-2′-deoxyuridine (EdU) was injected subcutaneously every two days for the first two weeks. There were no significant differences in cardiac size and function at baseline between C4KO and control mice. In control mice, running increased heart weight to tibial length ratio (HW/TL, 6.26±0.25 vs 7.37±0.75, p=0.01, n=5-9 per group), heart weight to body weight ratio (HW/BW, 4.08±0.40 vs 4.93±0.48, p=0.01), and cardiomyocyte (CM) size without affecting fractional shortening (FS), consistent with physiologic remodeling. There was also a nonsignificant trend to increased EdU+ CMs in the control exercised mice (2.96±2.34% vs 5.23±6.28%, p=0.44), suggestive of previously documented exercise-induced cardiomyogenesis. In contrast, running did not change HW/TL and CM size in C4KO mice (HW/TL, 6.44±0.48 vs 6.66±0.29, p=0.22, n= 0-13 per group) but reduced %FS (58.78±3.27 vs 53.67±4.59, p=0.03) and increased chamber size (LVIDs, 1.32±0.13 vs 1.50±0.17, p=0.032), suggesting maladaptive cardiac remodeling with exercise, confirming prior findings observed in a more extreme swim-exercise model. Rather than the expected increase, hearts from exercised C4KO mice had fewer EdU+ CMs compared to sedentary C4KO mice (3.76±2.60% vs 2.11±0.76%, p=0.05) and reduced expression of cell cycle genes Cdkn1b, Cyclin B1, Cdkn2a, and Ki-67. Conclusions: CITED4 is required for exercise-induced cardiomyogenesis, CM hypertrophy, and adaptive remodeling. CITED4 deficiency leads to maladaptive cardiac remodeling with physiologic stress.