Abstract 3991: The bHLH Transcription Factor CHF1/Hey2 Regulates Progression to Heart Failure Through Effects on Apoptotic DNA Fragmentation
CHF1/Hey2, a basic Helix-loop-helix transcription factor, plays a critical role in embryonic heart development and the development of hypertrophy. The mechanisms by which CHF1/Hey2 affects hypertrophy and progression to heart failure are poorly understood. To investigate the role of CHF1/Hey2 in the development of heart failure, we performed transverse aortic constriction on 12 week old male wild type (WT) and heterozygous knockout (HET) mice lacking one functional CHF1/Hey2 allele. We performed echocardiography to assess ventricular function and then assessed ventricular weight to body weight ratio and cardiac fibrosis by Masson-Trichrome staining at sacrifice. TUNEL was performed to demonstrate apoptosis in the heart. Real-time PCR was used to detect apoptosis related gene transcription. After aortic banding, Gravimetric analysis demonstrated a greater increase in ventricular weight to body weight ratio in HET mice compared with WT (7.13 vs. 6.05mg/g, p<0.05). HET mice developed increased left ventricular end-diastolic dimension compared with WT (4.05 vs. 3.62mm, p<0.05), which suggested eccentric hypertrophy in HET mice compared to the concentrichy-pertrophy in WT mice. HET mice also demonstrated increased susceptibility to heart failure. One week after aortic banding, WT mice showed no decrement in ejection fraction (EF, 62 vs. 66% sham, p=0.45). HET mice showed decompensated heart function as evidenced by significantly decreased EF (46 vs. 66% sham, p<0.01 and vs. 62% WT banding, p<0.01). HET mice developed extensive fibrosis in the heart after aortic banding when compared to WT mice. Quantification of TUNEL positive cells as a percentage of total nuclei demonstrated a significant increase of apoptosis in HET hearts compared to WT hearts (16.9 vs. 2.6%, p<0.05). After aortic banding, real-time PCR results showed more decrease of 45kD DNA fragmentation factor A (DFFA) expression in HET hearts than WT hearts (p<0.05), which is an important inhibitor of DNA fragmentation. Our findings demonstrate that CHF1/Hey2 loss of function facilitates an exacerbated cell death to pressure overload and accelerates development of fibrosis and progression to heart failure. The mechanism might involve decreased expression of the apoptosis inhibitor DFFA.