Taxol, a microtubule stabilizer, prevents ischemic ventricular arrhythmias in rats.
Microtubule integrity is important in cardio-protection, and microtubule disruption has been implicated in the response to ischemia in cardiac myocytes. However, the effects of Taxol, a common microtubule stabilizer, are still unknown in ischemic ventricular arrhythmias. The arrhythmia model was established in isolated rat hearts by regional ischemia, and myocardial infarction model by ischemia/reperfusion. Microtubule structure was immunohistochemically measured. The potential mechanisms were studied by measuring reactive oxygen species (ROS), activities of oxidative enzymes, intracellular calcium concentration ([Ca(2+) ](i) ) and Ca(2+) transients by using fluorometric determination, spectrophotometric assays and Fura-2-AM and Fluo-3-AM, respectively. The expression and activity of sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) was also examined using real-time polymerase chain reaction, Western blot and pyruvate/Nicotinamide adenine dinucleotide-coupled reaction. Our data showed that Taxol (0.1, 0.3 and 1 μM) effectively reduced the number of ventricular premature beats and the incidence and duration of ventricular tachycardia. The infarct size was also significantly reduced by Taxol (1 μM). At the same time, Taxol preserved the microtubule structure, increased the activity of mitochondrial electron transport chain complexes I and III, reduced ROS levels, decreased the rise in [Ca(2+)](i) and preserved the amplitude and decay times of Ca(2+) transients during ischemia. In addition, SERCA2a activity was preserved by Taxol during ischemia. In summary, Taxol prevents ischemic ventricular arrhythmias likely through ameliorating abnormal calcium homeostasis and decreasing the level of ROS. This study presents evidence that Taxol may be a potential novel therapy for ischemic ventricular arrhythmias.
Xiao
Junjie
J
Key Laboratory of Arrhythmias, Ministry of Education, East Hospital, Tongji University School of Medicine, Shanghai, China.
Cao
Huaming
H
Liang
Dandan
D
Liu
Ying
Y
Zhang
Hong
H
Zhao
Hong
H
Liu
Yi
Y
Li
Jun
J
Yan
Biao
B
Peng
Luying
L
Zhou
Zhaonian
Z
Chen
Yi-Han
YH
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control*; D002118:Calcium / Q000032:analysis; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D009203:Myocardial Infarction / Q000517:prevention & control*; D017239:Paclitaxel / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000032:analysis; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*
D045222:Electron Transport Chain Complex Proteins; D017382:Reactive Oxygen Species; D050257:Tubulin Modulators; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D017239:Paclitaxel; D002118:Calcium