Characterization of a Critical Role for CFTR Chloride Channels in Cardioprotection Against Ischemia/reperfusion Injury

Overview

Journal Acta Pharmacol Sin

Specialty Pharmacology

Date 2011 Jun 7

PMID 21642951

Citations 9

Authors

Sunny Yang Xiang

Linda L Ye

Li-lu Marie Duan

Li-Hui Liu

Zhi-Dong Ge

John A Auchampach

Garrett J Gross

Dayue Darrel Duan

Affiliations

Soon will be listed here.

Abstract

Aim: To further characterize the functional role of cystic fibrosis transmembrane conductance regulator (CFTR) in early and late (second window) ischemic preconditioning (IPC)- and postconditioning (POC)-mediated cardioprotection against ischemia/reperfusion (I/R) injury.

Methods: CFTR knockout (CFTR(-/-)) mice and age- and gender-matched wild-type (CFTR(+/+)) and heterozygous (CFTR(+/-)) mice were used. In in vivo studies, the animals were subjected to a 30-min coronary occlusion followed by a 40-min reperfusion. In ex vivo (isolate heart) studies, a 45-min global ischemia was applied. To evaluate apoptosis, the level of activated caspase 3 and TdT-mediated dUTP-X nick end labeling (TUNEL) were examined.

Results: In the in vivo I/R models, early IPC significantly reduced the myocardial infarct size in wild-type (CFTR(+/+)) (from 40.4% ± 5.3% to 10.4% ± 2.0%, n=8, P<0.001) and heterozygous (CFTR(+/-)) littermates (from 39.4% ± 2.4% to 15.4% ± 5.1%, n=6, P<0.001) but failed to protect CFTR knockout (CFTR(-/-)) mice from I/R induced myocardial infarction (46.9% ± 6.2% vs 55.5% ± 7.8%, n=6, P>0.5). Similar results were observed in the in vivo late IPC experiments. Furthermore, in both in vivo and ex vivo I/R models, POC significantly reduced myocardial infarction in wild-type mice, but not in CFTR knockout mice. In ex vivo I/R models, targeted inactivation of CFTR gene abolished the protective effects of IPC against I/R-induced apoptosis.

Conclusion: These results provide compelling evidence for a critical role for CFTR Cl(-) channels in IPC- and POC-mediated cardioprotection against I/R-induced myocardial injury.

Citing Articles

The Distribution and Role of the CFTR Protein in the Intracellular Compartments.

Lukasiak A, Zajac M Membranes (Basel). 2021; 11(11).

PMID: 34832033 PMC: 8618639. DOI: 10.3390/membranes11110804.

Chloride channel blocker IAA-94 increases myocardial infarction by reducing calcium retention capacity of the cardiac mitochondria.

Ponnalagu D, Hussain A, Thanawala R, Meka J, Bednarczyk P, Feng Y Life Sci. 2019; 235:116841.

PMID: 31494173 PMC: 7664129. DOI: 10.1016/j.lfs.2019.116841.

CFTR prevents neuronal apoptosis following cerebral ischemia reperfusion via regulating mitochondrial oxidative stress.

Zhang Y, Zhang Y, Xiao Z, Zhang Y, Zhang J, Li Z J Mol Med (Berl). 2018; 96(7):611-620.

PMID: 29761302 DOI: 10.1007/s00109-018-1649-2.

Heart-specific overexpression of the human short CLC-3 chloride channel isoform limits myocardial ischemia-induced ERP and QT prolongation.

Yu Y, Ye L, Li Y, Burkin D, Duan D Int J Cardiol. 2016; 214:218-24.

PMID: 27064645 PMC: 4862918. DOI: 10.1016/j.ijcard.2016.03.191.

Characterization of Cardiac Anoctamin1 Ca²⁺-Activated Chloride Channels and Functional Role in Ischemia-Induced Arrhythmias.

Ye Z, Wu M, Wang C, Li Y, Yu C, Gong Y J Cell Physiol. 2014; 230(2):337-46.

PMID: 24962810 PMC: 4293372. DOI: 10.1002/jcp.24709.

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