The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ATP-binding cassette (ABC) transporters superfamily, which functions as not only a transport but also a Cl- channel gated by protein kinase-dependent phosphorylation and cycles of ATP binding and hydrolysis. While the biophysical and pharmacological properties of the CFTR Cl- channels have been well characterized, the functional role of CFTR in the heart in the context of health and disease remains elusive. Recent clinical evidence points to a potential role of CFTR in heart failure (HF) but the exact functional and clinical significance of cardiac CFTR in myocardial hypertrophy and HF has not been studied. The long-term goal of our study is to determine the novel cardioprotective role of cardiac CFTR in cardiac hypertrophy and HF and to investigate the underlying molecular mechanisms. The short-term goal is to explore the functional and mechanistic bases of CFTR in the protection of cardiac myocytes against oxidative stress damage inflicted during myocardial hypertrophy and heart failure. To achieve these goals this proposal addresses the following specific aims: 1) to determine the functional role of CFTR in cardiac hypertrophy and failure through the demonstration of that targeted inactivation of CFTR gene causes a loss of compensatory response of cardiac function during the development of pathological myocardial hypertrophy and accelerate the progression of HF;2) to determine whether CFTR is involved in redox regulation by demonstration of that a) CFTR is expressed on mitochondria, b) targeted inactivation of CFTR decreases mitochondrial concentration of 3- glutamyl-cysteinyl-glycine ([GSH]mito), and c) CFTR-mediated changes in [GSH]mito are closely coupled to regulation of mitochondrial function and cell viability under hypertrophy-induced oxidative stress. Experimental approaches will involve the use of CFTR knockout mouse, isolated working heart preparations, pressure-overload model of myocardial hypertrophy and HF, serial echocardiography, molecular biological and immunological techniques and mitochondrial GSH measurement and functional assays. The significance is that these studies will gain crucial evidence for the novel function of CFTR in protection of the heart against cardiac hypertrophy and failure and substantial knowledge on the novel mechanisms of redox regulation by CFTR-mediated mitochondrial GSH homeostasis, which will setup the stage for further understanding of the function and mechanism for the sarcolemmal and mitochondrial CFTR interactomes in the heart and pave a new path to the identification of novel therapeutic targets and thus translate these preclinical findings into clinical treatment of HF.

Public Health Relevance

Heart diseases remain a major cause of human death in the United States. Clinical care for heart diseases is usually intensive and involves long term hospitalization, especially with heart failure, which creates a significant burden on the health care system. This proposal is to use state-of-the-art techniques to study how the heart can be protected from damages caused by increased work load. We focus on the novel function and molecular mechanism to protect the mitochondria of heart cells. As a result, it will provide new and crucial information for better understanding of the cause of heart disease and also new drug targets for the treatment of heart diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL106256-01
Application #
8032346
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Wang, Lan-Hsiang
Project Start
2011-01-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
1
Fiscal Year
2011
Total Cost
$210,680
Indirect Cost
Name
University of Nevada Reno
Department
Pharmacology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Yu, Ying; Ye, Linda; Li, Yi-Gang et al. (2016) Heart-specific overexpression of the human short CLC-3 chloride channel isoform limits myocardial ischemia-induced ERP and QT prolongation. Int J Cardiol 214:218-24
Ye, Zhen; Wu, Ming-Ming; Wang, Chun-Yu et al. (2015) Characterization of Cardiac Anoctamin1 Ca²?-Activated Chloride Channels and Functional Role in Ischemia-Induced Arrhythmias. J Cell Physiol 230:337-46
Han, Yeshan; Li, Li; Zhang, Yaping et al. (2015) Phenomics of Vascular Disease: The Systematic Approach to the Combination Therapy. Curr Vasc Pharmacol 13:433-40
Wu, Ming-Ming; Lou, Jie; Song, Bin-Lin et al. (2014) Hypoxia augments the calcium-activated chloride current carried by anoctamin-1 in cardiac vascular endothelial cells of neonatal mice. Br J Pharmacol 171:3680-92
Zhang, Ya-Ping; Zuo, Xiao-Cong; Huang, Zhi-Jun et al. (2013) The impact of blood pressure on kidney function in the elderly: a cross-sectional study. Kidney Blood Press Res 38:205-16
Wang, Wei Eric; Yang, Dezhong; Li, Liangpeng et al. (2013) Prolyl hydroxylase domain protein 2 silencing enhances the survival and paracrine function of transplanted adipose-derived stem cells in infarcted myocardium. Circ Res 113:288-300
Zhang, Ya-ping; Zhang, Hao; Duan, Dayue Darrel (2013) Chloride channels in stroke. Acta Pharmacol Sin 34:17-23
Duan, Dayue Darrel (2013) Phenomics of cardiac chloride channels. Compr Physiol 3:667-92
Duan, Dayue Darrel; Wang, Guangyu (2012) Double the keys, double the control: coupled phosphorylation sites provide novel molecular targets for precise control of ion channel function. Focus on ""Differential regulation of a CLC anion channel by SPAK kinase ortholog-mediated multisite phosphoryl Am J Physiol Cell Physiol 302:C1699-701
Wang, Guangyu; Duan, Dayue Darrel (2012) Regulation of activation and processing of the cystic fibrosis transmembrane conductance regulator (CFTR) by a complex electrostatic interaction between the regulatory domain and cytoplasmic loop 3. J Biol Chem 287:40484-92

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