Defining a role for the cystic fibrosis transmembrane conductance regulator in the heart

cystic fibrosis;Cystic fibrosis transmembrane conductance regulator (CFTR);cardiac myocyte;heart

Sellers, Zachary M.

关键词: cystic fibrosis;    Cystic fibrosis transmembrane conductance regulator (CFTR);    cardiac myocyte;    heart;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/15519/1_Sellers_Zachary.pdf?sequence=2&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

While cystic fibrosis (CF) is commonly thought of as a lung disease, since it’s first description 70 years ago we have come to understand that loss of CFTR (cystic fibrosis transmembrane conductance regulator) function affects numerous tissues and systems throughout the body.Concerning the heart, right ventricular dysfunction secondary to pulmonary abnormalities has long been recognized.However, the issue as to whether loss of CFTR function causes primary disturbances in the heart has remained an unsolved and often debated question.Thus, the goal of the research presented herein was to answer two fundamental questions, 1) “Does CFTR play a physiological role in heart function?,” and 2) “What direct impact does loss of CFTR activity have on heart function?”These are particularly timely questions now as CF patients are living longer and the development of CFTR modulators is being pursued with increased vigor.Thus, an understanding if CF patients will be at increased risk for heart disease and whether new therapies may affect heart function are of direct relevance to the care of these individuals.To begin to answer the questions presented we have examined how modulation of CFTR affects neonatal ventricular cardiomyocyte contraction rate.We found that CFTR is involved in the regulation of both baseline and beta-adrenergic stimulated contraction rate.Additionally, loss of CFTR activity, whether acutely or chronically, leads to modulation of intracellular signaling molecules and other Cl- channels, which in some cases can completely compensate for this loss, while in other cases cannot.Finally, in vivo examination of heart function in CFTR KO mice has elucidated disturbances in heart structure and function, which may translate into problems experienced by CF patients.In sum, this work presents a significant expansion of our understanding regarding the role of CFTR in heart function and highlights the need to further pursue a more in-depth analysis of the health of the heart in CF patients.