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

摘要： <正> Aim:The occurrence of ventricular fibrillation (VF) is dependent on the deteriora-tion of channelopathy in the myocardium.It is interesting to investigate molecularchanges in relation to abrupt appearance of VF on reperfusion.We aimed to studywhether changes in the expression of FKBP12.6 and SERCA2a and the endothelin(ET) system on reperfusion against ischemia were related to the rapid occurrenceof VF and whether CPU86017,a class Ⅲ antiarrhythmic agent which blocks I_(Kr),I_(Ks).and I_(Ca.L),suppressed VF by correcting the molecular changes on reperfusion.Methods:Cardiomyopathy (CM) was produced by 0.4 mg/kg sc L-thyroxin for10 d in rats,and subjected to 10 min coronary artery ligation/reperfusion on d11.Expressions of the Ca~(2+) handling and ET system and calcium transients wereconducted and CPU86017 was injected (4 mg/kg,sc) on d 6-10.Results:A highincidence of VF was found on reperfusion of the rat CM hearts,but there was noVF before reperfusion.The elevation of diastolic calcium was significant in theCM myocytes and exhibited abnormality of the Ca~(2+) handling system.The rapiddownregulation of mRNA and the protein expression of FKBP12.6 and SERCA2awere found on reperfusion in association with the upregulation of the expressionof the endothelin-converting enzyme (ECE) and protein kinase A (PKA),in contrast,no change in the ryanodine type 2 receptor (RyR2),phospholamban (PLB),endothelin A receptor (ET_AR),and iNOS was found.CPU86017 removed thesechanges and suppressed VF.Conclusion:Abrupt changes in the expression ofFKBP12.6,SERCA2a,PKA,and ECE on reperfusion against ischemia,which areresponsible for the rapid occurrence of VF,have been observed.These changesare effectively prevented by CPU86017. （共10頁）