Downregulated FKBP12.6 expression and upregulated endothelin signaling contribute to elevated diastolic calcium and arrhythmogenesis in rat cardiomyopathy produced by l-thyroxin.
BACKGROUND
Dissociation of FKBP12.6 from RyR2 is considered as an important molecular event resulting in calcium leak and an increased risk in arrhythmogenesis. We hypothesized that augmented ventricular fibrillation (VF) on reperfusion of rat cardiomyopathy induced by l-thyroxin may result from elevated diastolic Ca(2+) levels due to dissociation (downregulation) of FKBP12.6 and upregulation of endothelin (ET-1) signaling pathway.


METHODS
Rats were treated with l-thyroxin (0.4 mg/kg, s.c.) for 10 days. Dajisentan (CPU0213), a dual endothelin receptor antagonist (100 mg/kg p.o.), or propranolol was administered on day 6 to 10. Susceptibility to VF was evaluated on ischemia/reperfusion episode. mRNA expression of FKBP12.6, and ET-1 levels were determined. Calcium transients and FKBP12.6 immunohistochemistry were measured by confocal microscopy in isolated cardiomyocytes from cardiomyopathy.


RESULTS
Cardiomyopathy induced by l-thyroxin resulted in an increased susceptibility to VF on ischemia/reperfusion. Upregulated mRNA expression of RyR2 and PKA in association with downregulated FKBP12.6 expression was found in l-thyroxin-treated rats compared to controls. Calcium transients evoked by field electrical stimulation showed an increase in Ca(2+) by +75% during diastole. An increase in ET-1 (ng/mg protein) (+36.6%) and mRNA abundance of preproET-1 were found in the left ventricle. A decreased mRNA ratio of FKBP12.6 to RyR2 likely reflected dissociation of FKBP12.6 in cardiomyopathy. These changes were normalized by Dajisentan, comparable to propranolol.


CONCLUSIONS
Increased susceptibility to VF in l-thyroxin-induced cardiomyopathy is related to increase in diastolic Ca(2+) levels, resulting from downregulated FKBP12.6 and upregulated ET system. ET antagonism might be useful in settings of FKBP12.6 dissociation.
Zhang
Yuan
Y
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, 210009, China.
Huang
Zhi-Jiang
ZJ
Dai
De-Zai
DZ
Feng
Yu
Y
Na
Tao
T
Tang
Xiao-Yun
XY
Dai
Yin
Y
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000139:chemically induced / Q000453:epidemiology / Q000378:metabolism*; D003971:Diastole / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D019332:Endothelin-1 / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013974:Thyroxine / Q000633:toxicity; D015854:Up-Regulation / Q000502:physiology; D014693:Ventricular Fibrillation / Q000453:epidemiology / Q000378:metabolism*
D019332:Endothelin-1; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D013974:Thyroxine; D002118:Calcium