Abrupt changes in FKBP12.6 and SERCA2a expression contribute to sudden occurrence of ventricular fibrillation on reperfusion and are prevented by CPU86017.
OBJECTIVE
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 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 for 10 d in rats, and subjected to 10 min coronary artery ligation/reperfusion on d 11. Expressions of the Ca2+ 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 Ca2+ 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 (ECE) 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 VF.


CONCLUSIONS
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.
Na
Tao
T
Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
Huang
Zhi-Jiang
ZJ
Dai
De-Zai
DZ
Zhang
Yuan
Y
Dai
Yin
Y
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001599:Berberine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015424:Reperfusion; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000378:metabolism*; D013974:Thyroxine / Q000009:adverse effects; D014693:Ventricular Fibrillation / Q000378:metabolism*
C400084:4-chlorobenzyltetrahydroberberine; D000889:Anti-Arrhythmia Agents; D001599:Berberine; D052247:Nitric Oxide Synthase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D013974:Thyroxine; D002118:Calcium