Abrupt changes in FKBP12.6 and SERCA2a expression contribute to sudden occurrence of ventricular fibrillation on reperfusion and are prevented by CPU86017  

作　　者：Tao NA Zhi-jiang HUANG De-zai DAI Yuan ZHANG Yin DAI 

机构地区：[1]Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China

出　　处：《Acta Pharmacologica Sinica》2007年第6期773-782,共10页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(№ 30572193 and 30230170)

摘　　要：Aim： The occurrence of ventricular fibrillation （VF） is dependent on the deterioration of channelopathy in the myocardium. It is interesting to investigate molecular changes in relation to abrupt appearance of VF on reperfusion. We aimed to study whether changes in the expression of FKBP12.6 and SERCA2a and the endothelin （ET） system on reperfusion against ischemia were related to the rapid occurrence of VF and whether CPU86017, a class III antiarrhythmic agent which blocks Ikr.IKs. and ICa.L, suppressed VF by correcting the molecular changes on reperfusion. Methods： Cardiomyopathy （CM） was produced by 0.4 mg/kg sc L-thyroxin for 10 d in rats, and subjected to 10 min coronary artery ligation/reperfusion on d 11. Expressions of the Ca^2＋ handling and ET system and calcium transients were conducted and CPU86017 was injected （4 mg/kg, sc） on d 6-10. Results： A high incidence of VF was found on reperfusion of the rat CM hearts, but there was no VF before reperfusion. The elevation of diastolic calcium was significant in the CM myocytes and exhibited abnormality of the Ca^2＋ handling system. The rapid downregulation of mRNA and the protein expression of FKBP12.6 and SERCA2a were found on reperfusion in association with the upregulation of the expression of the endothelin-converting enzyme 0ECE） and protein kinase A （PKA）, in contrast, no change in the ryanodine type 2 receptor （RyR2）, phospholamban （PLB）, endothelin A receptor （ETAR）, and iNOS was found. CPU86017 removed these changes and suppressed VE Conclusion： Abrupt changes in the expression of FKBP12.6, SERCA2a, PKA, and ECE on reperfusion against ischemia, which are responsible for the rapid occurrence of VF, have been observed. These changes are effectively prevented by CPU86017.Aim： The occurrence of ventricular fibrillation （VF） is dependent on the deterioration of channelopathy in the myocardium. It is interesting to investigate molecular changes in relation to abrupt appearance of VF on reperfusion. We aimed to study whether changes in the expression of FKBP12.6 and SERCA2a and the endothelin （ET） system on reperfusion against ischemia were related to the rapid occurrence of VF and whether CPU86017, a class III antiarrhythmic agent which blocks Ikr.IKs. and ICa.L, suppressed VF by correcting the molecular changes on reperfusion. Methods： Cardiomyopathy （CM） was produced by 0.4 mg/kg sc L-thyroxin for 10 d in rats, and subjected to 10 min coronary artery ligation/reperfusion on d 11. Expressions of the Ca^2＋ handling and ET system and calcium transients were conducted and CPU86017 was injected （4 mg/kg, sc） on d 6-10. Results： A high incidence of VF was found on reperfusion of the rat CM hearts, but there was no VF before reperfusion. The elevation of diastolic calcium was significant in the CM myocytes and exhibited abnormality of the Ca^2＋ handling system. The rapid downregulation of mRNA and the protein expression of FKBP12.6 and SERCA2a were found on reperfusion in association with the upregulation of the expression of the endothelin-converting enzyme 0ECE） and protein kinase A （PKA）, in contrast, no change in the ryanodine type 2 receptor （RyR2）, phospholamban （PLB）, endothelin A receptor （ETAR）, and iNOS was found. CPU86017 removed these changes and suppressed VE Conclusion： Abrupt changes in the expression of FKBP12.6, SERCA2a, PKA, and ECE on reperfusion against ischemia, which are responsible for the rapid occurrence of VF, have been observed. These changes are effectively prevented by CPU86017.

关 键 词：sudden cardiac death ventricular fibrillation ENDOTHELIN FKBPI2.6 SERCA2A proteinkinase A CPU86017 cardiomyopathy L-THYROXIN endothelin-converting enzyme 

分 类 号：R541[医药卫生—心血管疾病]