Decreased FKBP12.6 expression and enhanced endothelin receptor signaling associated with arrhymogenesis in myocardial infarction rats.
An increased propensity towards cardiac arrhythmias and aggravated heart function is observed in myocardial infarction (MI), the development of which is associated with the calcium handling system in the myocardium. It was hypothesized that the abnormal changes in the MI model may be a consequence of the abnormal expression and function of the RyR2-FKBP12.6 channel complex and that these abnormalities may be related to an over-activated endothelin (ET) system. Salvianolic acid B is expected to suppress life-threatening arrhythmias and to restore the abnormality of the RyR2-FKBP12.6 complex in rats. MI was produced by ligating the coronary artery for 4 weeks. Salvianolic acid B (100 mg/kg/day, p.o. for 4 weeks) was administered to rats 0.5 h before surgery. Measurements of cardiac arrhythmias, cardiac function, calcium transient, cardiac calcium release channel handling proteins and the endothelin system were conducted. The aggravated arrhythmia and compromised cardiac function in MI rats was accompanied by elevated diastolic Ca(2+) levels in the cytosol and a significant down-regulation of expression of RyR2-FKBP12.6. These were closely linked with an over-activated ET pathway in the myocardium. After a 4-week treatment with salvianolic acid B, all abnormalities were reversed significantly. Salvianolic acid B was capable of normalizing FKBP12.6 expression levels and decreasing the propensity towards arrhythmias by attenuating the up-regulated ET pathway.
Institute of Chinese Herb Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, PRC.
Haibo
H
He
Mengqiong
M
Shi
Xiaowei
X
Zeng
Xianzhe
X
Yang
Jun
J
Yang
Limao
L
Wu
Lianda
L
Li
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D001572:Benzofurans / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053630:Depsides
D001572:Benzofurans; D002118:Calcium; D004365:Drugs, Chinese Herbal; D017466:Receptors, Endothelin; D019837:Ryanodine Receptor Calcium Release Channel; D022021:Tacrolimus Binding Proteins; C076944:salvianolic acid B; D053630:Depsides; C403484:tacrolimus binding protein 1B