Abstract 18267: Novel Cardioprotective Function of CFTR Chloride Channels Agaisnt Myocardial Hypertrophy and Heart Failure
Background: CFTR is a member of the ATP-binding cassette (ABC) transporters and encodes a PKC- and PKA-activated Cl- channel in the heart. Recent studies found that the expression of the matured CFTR protein in human failing hearts decreased significantly to 52% of CFTR levels in nonfailing controls. A pediatric patient with ΔF508CFTR mutation died of heart failure (HF) with lethal myocardial lesion but no significant pulmonary fibrosis. The exact functional and clinical significance of CFTR in myocardial hypertrophy (CH) and HF is currently not clear. In this study we will test our hypothesis that CFTR may play a crucial protective role against HF.
Methods: Minimally-invasive transverse aorta binding (MTAB) pressure-overload model of CH and HF was applied to CFTR-knockout (CFTR-/-) mice and their age- and gender-matched wild-type (CFTR+/+) and heterozygous (CFTR+/-) littermates. The functional and histological changes of the hearts subjected to MTAB were examined.
Results: MTAB induced a time-dependent development of CH in CFTR+/+ and CFTR-/- mice, as indicated by a significant increase in both end-diastolic and end-systolic left ventricular (LV) mass and wall thickness. During the 9-week period of MTAB, however, the increase in LV mass and LV cavity diameters in the CFTR-/- mice was significantly larger with a much more rapid pace than that in the CFTR+/+ mice, indicating a faster development of dilated cardiomyopathy in the CFTR-/- mice. In sharp contrast to the strong compensation capacity to maintain cardiac function of the CFTR+/+ mice during the 9-week period of MTAB (%FS changed from 62±1.1 to 43±2, a 22.3±2% reduction, n=3) no significant compensation period but a progressively reduced %FS was observed in the CFTR-/- mice. In 9 weeks of MTAB, %FS of the CFTR-/- mice was reduced from 60±1 to 19±3 (n=3, a 69.3±4% reduction, P<0.001 vs CFTR+/+ mice).
Conclusion: Targeted disruption of CFTR gene significantly changed the pressure overload-induced remodeling process. The loss of CFTR function may be responsible for the loss of compensation and the faster progression of dilated HF, implicating an important protective role of CFTR in the structural and functional remodeling of the heart in response to pressure overload.
- © 2011 by American Heart Association, Inc.