Redox and activation of protein kinase A dysregulates calcium homeostasis in pulmonary vein cardiomyocytes of chronic kidney disease

Shih Yu Huang, Yao Chang Chen, Yu Hsun Kao, Ming Hsiung Hsieh, Yung Kuo Lin, Shih Ann Chen, Yi Jen Chen

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background-Chronic kidney disease (CKD) increases the occurrence of atrial fibrillation and pulmonary vein (PV) arrhythmogenesis. Calcium dysregulation and reactive oxygen species (ROS) enhance PV arrhythmogenic activity. The purposes of this study were to investigate whether CKD modulates PV electrical activity through dysregulation of calcium homeostasis and ROS. Methods and Results-Biochemical and electrocardiographic studies were conducted in rabbits with and without CKD (induced by 150 mg/kg per day neomycin sulfate and 500 mg/kg per day cefazolin). Confocal microscopy with fluorescence and a whole-cell patch clamp were applied to study calcium homeostasis and electrical activities in control and CKD isolated single PV cardiomyocytes with or without treatment with H89 (1 μmol/L, a protein kinase A inhibitor) and MPG (N-[2-mercaptopropionyl] glycine; 100 μmol/L, a ROS scavenger). The ROS in mitochondria and cytosol were evaluated via intracellular dye fluorescence and lipid peroxidation. CKD rabbits had excessive atrial premature captures over those of control rabbits. Compared with the control, CKD PV cardiomyocytes had a faster beating rate and larger calcium transient amplitudes, sarcoplasmic reticulum calcium contents, sodium/calcium exchanger currents, and late sodium currents but smaller L-type calcium current densities. CKD PV cardiomyocytes had a higher frequency and longer duration of calcium sparks and more ROS in the mitochondria and cytosol than did controls. Moreover, H89 suppressed all calcium sparks in CKD PV cardiomyocytes, and H89- and MPG-treated CKD PV cardiomyocytes had similar calcium transients compared with control PV cardiomyocytes. Conclusions-CKD increases PV arrhythmogenesis with enhanced calcium-handling abnormalities through activation of protein kinase A and ROS.

Original languageEnglish
Article numbere005701
JournalJournal of the American Heart Association
Volume6
Issue number7
DOIs
Publication statusPublished - Jul 1 2017

Fingerprint

Pulmonary Veins
Cyclic AMP-Dependent Protein Kinases
Chronic Renal Insufficiency
Cardiac Myocytes
Oxidation-Reduction
Homeostasis
Calcium
Reactive Oxygen Species
Calcium Signaling
Rabbits
Cytosol
Mitochondria
Fluorescence
Sodium-Calcium Exchanger
Cefazolin
Neomycin
Sarcoplasmic Reticulum
Protein Kinase Inhibitors
Confocal Microscopy
Glycine

Keywords

  • Atrial fibrillation
  • Calcium regulation
  • Chronic kidney disease
  • Pulmonary vein
  • Reactive oxygen species

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

@article{860eee8d9a93456a92368c8a781d35cf,
title = "Redox and activation of protein kinase A dysregulates calcium homeostasis in pulmonary vein cardiomyocytes of chronic kidney disease",
abstract = "Background-Chronic kidney disease (CKD) increases the occurrence of atrial fibrillation and pulmonary vein (PV) arrhythmogenesis. Calcium dysregulation and reactive oxygen species (ROS) enhance PV arrhythmogenic activity. The purposes of this study were to investigate whether CKD modulates PV electrical activity through dysregulation of calcium homeostasis and ROS. Methods and Results-Biochemical and electrocardiographic studies were conducted in rabbits with and without CKD (induced by 150 mg/kg per day neomycin sulfate and 500 mg/kg per day cefazolin). Confocal microscopy with fluorescence and a whole-cell patch clamp were applied to study calcium homeostasis and electrical activities in control and CKD isolated single PV cardiomyocytes with or without treatment with H89 (1 μmol/L, a protein kinase A inhibitor) and MPG (N-[2-mercaptopropionyl] glycine; 100 μmol/L, a ROS scavenger). The ROS in mitochondria and cytosol were evaluated via intracellular dye fluorescence and lipid peroxidation. CKD rabbits had excessive atrial premature captures over those of control rabbits. Compared with the control, CKD PV cardiomyocytes had a faster beating rate and larger calcium transient amplitudes, sarcoplasmic reticulum calcium contents, sodium/calcium exchanger currents, and late sodium currents but smaller L-type calcium current densities. CKD PV cardiomyocytes had a higher frequency and longer duration of calcium sparks and more ROS in the mitochondria and cytosol than did controls. Moreover, H89 suppressed all calcium sparks in CKD PV cardiomyocytes, and H89- and MPG-treated CKD PV cardiomyocytes had similar calcium transients compared with control PV cardiomyocytes. Conclusions-CKD increases PV arrhythmogenesis with enhanced calcium-handling abnormalities through activation of protein kinase A and ROS.",
keywords = "Atrial fibrillation, Calcium regulation, Chronic kidney disease, Pulmonary vein, Reactive oxygen species",
author = "Huang, {Shih Yu} and Chen, {Yao Chang} and Kao, {Yu Hsun} and Hsieh, {Ming Hsiung} and Lin, {Yung Kuo} and Chen, {Shih Ann} and Chen, {Yi Jen}",
year = "2017",
month = "7",
day = "1",
doi = "10.1161/JAHA.117.005701",
language = "English",
volume = "6",
journal = "Journal of the American Heart Association",
issn = "2047-9980",
publisher = "Wiley-Blackwell",
number = "7",

}

TY - JOUR

T1 - Redox and activation of protein kinase A dysregulates calcium homeostasis in pulmonary vein cardiomyocytes of chronic kidney disease

AU - Huang, Shih Yu

AU - Chen, Yao Chang

AU - Kao, Yu Hsun

AU - Hsieh, Ming Hsiung

AU - Lin, Yung Kuo

AU - Chen, Shih Ann

AU - Chen, Yi Jen

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Background-Chronic kidney disease (CKD) increases the occurrence of atrial fibrillation and pulmonary vein (PV) arrhythmogenesis. Calcium dysregulation and reactive oxygen species (ROS) enhance PV arrhythmogenic activity. The purposes of this study were to investigate whether CKD modulates PV electrical activity through dysregulation of calcium homeostasis and ROS. Methods and Results-Biochemical and electrocardiographic studies were conducted in rabbits with and without CKD (induced by 150 mg/kg per day neomycin sulfate and 500 mg/kg per day cefazolin). Confocal microscopy with fluorescence and a whole-cell patch clamp were applied to study calcium homeostasis and electrical activities in control and CKD isolated single PV cardiomyocytes with or without treatment with H89 (1 μmol/L, a protein kinase A inhibitor) and MPG (N-[2-mercaptopropionyl] glycine; 100 μmol/L, a ROS scavenger). The ROS in mitochondria and cytosol were evaluated via intracellular dye fluorescence and lipid peroxidation. CKD rabbits had excessive atrial premature captures over those of control rabbits. Compared with the control, CKD PV cardiomyocytes had a faster beating rate and larger calcium transient amplitudes, sarcoplasmic reticulum calcium contents, sodium/calcium exchanger currents, and late sodium currents but smaller L-type calcium current densities. CKD PV cardiomyocytes had a higher frequency and longer duration of calcium sparks and more ROS in the mitochondria and cytosol than did controls. Moreover, H89 suppressed all calcium sparks in CKD PV cardiomyocytes, and H89- and MPG-treated CKD PV cardiomyocytes had similar calcium transients compared with control PV cardiomyocytes. Conclusions-CKD increases PV arrhythmogenesis with enhanced calcium-handling abnormalities through activation of protein kinase A and ROS.

AB - Background-Chronic kidney disease (CKD) increases the occurrence of atrial fibrillation and pulmonary vein (PV) arrhythmogenesis. Calcium dysregulation and reactive oxygen species (ROS) enhance PV arrhythmogenic activity. The purposes of this study were to investigate whether CKD modulates PV electrical activity through dysregulation of calcium homeostasis and ROS. Methods and Results-Biochemical and electrocardiographic studies were conducted in rabbits with and without CKD (induced by 150 mg/kg per day neomycin sulfate and 500 mg/kg per day cefazolin). Confocal microscopy with fluorescence and a whole-cell patch clamp were applied to study calcium homeostasis and electrical activities in control and CKD isolated single PV cardiomyocytes with or without treatment with H89 (1 μmol/L, a protein kinase A inhibitor) and MPG (N-[2-mercaptopropionyl] glycine; 100 μmol/L, a ROS scavenger). The ROS in mitochondria and cytosol were evaluated via intracellular dye fluorescence and lipid peroxidation. CKD rabbits had excessive atrial premature captures over those of control rabbits. Compared with the control, CKD PV cardiomyocytes had a faster beating rate and larger calcium transient amplitudes, sarcoplasmic reticulum calcium contents, sodium/calcium exchanger currents, and late sodium currents but smaller L-type calcium current densities. CKD PV cardiomyocytes had a higher frequency and longer duration of calcium sparks and more ROS in the mitochondria and cytosol than did controls. Moreover, H89 suppressed all calcium sparks in CKD PV cardiomyocytes, and H89- and MPG-treated CKD PV cardiomyocytes had similar calcium transients compared with control PV cardiomyocytes. Conclusions-CKD increases PV arrhythmogenesis with enhanced calcium-handling abnormalities through activation of protein kinase A and ROS.

KW - Atrial fibrillation

KW - Calcium regulation

KW - Chronic kidney disease

KW - Pulmonary vein

KW - Reactive oxygen species

UR - http://www.scopus.com/inward/record.url?scp=85025439981&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85025439981&partnerID=8YFLogxK

U2 - 10.1161/JAHA.117.005701

DO - 10.1161/JAHA.117.005701

M3 - Article

AN - SCOPUS:85025439981

VL - 6

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 7

M1 - e005701

ER -