Cystic Fibrosis Transmembrane Conductance Regulator Is Heterologously Expressed in Human Heart

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP‐binding cassette transporter family and is a chloride channel protein. CFTR dysfunction is considered the major factor in development of cystic fibrosis. While CFTR research has focused primarily on its role in the lung and intestinal epithelia, CFTR is also present in a variety of tissues including heart. Information regarding CFTR's role in heart function is limited but possible roles for CFTR in myocardial protection and progression of heart disease have been implicated.Using biomaterials in the Duke Human Heart Repository (DHHR), an extensive and well‐curated source of human cardiac samples, we have initiated molecular and genetic studies focused on the CFTR locus in human hearts. Using a next generation sequence panel customized for CFTR gene (Ion Torrent) we obtained CFTR sequences from 48 genomic DNA samples in the DHHR (3 groups, n=16, i) no heart failure (NF), ii) non‐ischemic cardiomyopathy (NICM), and iii) ischemic cardiomyopathy (ICM)). Sequences mapping to a putative CFTR enhancer element emerged as differential between DNA from hearts +/− end‐stage heart failure. Since these changes map to a region which may control CFTR gene expression, we hypothesized that there may be differential protein expression between failing and non‐failing human hearts. To test this hypothesis we evaluated CFTR protein (using antibody 570, John Riordan, UNC) in human heart samples via western blot analysis. CFTR protein was present in all heart regions evaluated. In tissues from right ventricle (RV) and left ventricle (LV), CFTR protein expression was consistently higher in NF samples than in corresponding samples with heart failure. The highest level of CFTR expression was observed in the right atrium (RA) from ICM patient samples. The levels of CFTR may diminish early in the transition of healthy myocardium to early heart disease as indicated by the analysis of NF samples with and without left ventricular hypertrophy (LVH) an early indication of heart disease, where CFTR expression was dramatically less in LVH patients. Although preliminary, this may indicate loss of CFTR may occur early in the progression and initiation of heart disease and could potentially be part of early diagnostic testing if this effect proves to be a valid indicator of early heart disease. The mechanism of loss of CFTR in failed tissue is an ongoing line of investigation to assess whether CFTR affects progression of heart disease. As potential targets for intervention in the CFTR regulation pathway we are investigating CFTR turnover and phosphorylation in cardiac tissues as well as functional aspects of low expression or over‐expression especially as it relates to mitochondrial function and calcium handling in the intact, functioning myocardium.Support or Funding InformationThis research was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Numbers UL1TR001117 and UL1TR001111. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of HealthThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.