Berbamine protects the heart from ischemia/reperfusion injury by maintaining cytosolic Ca(2+) homeostasis and preventing calpain activation.
BACKGROUND
Berbamine, a natural compound from Barberry, was reported to protect myocardium from ischemia/reperfusion (I/R) injury, but the underlying mechanisms are largely unknown.


RESULTS
Berbamine pretreatment from 10 to 100nmol/L concentration-dependently improved post-ischemic myocardial function. Similar protection was confirmed in isolated cardiomyocytes characterized by the attenuation of I/R-induced intracellular free Ca(2+) concentration ([Ca(2+)](i)) overloading and the depression of cell shortening and Ca(2+) transients, which were partially mimicked but not augmented by calpain inhibitor calpeptin and abolished by mitochondrial ATP-sensitive potassium (mitoK(ATP) channel inhibitor 5-hydroxydecanoate (5-HD) and phosphoinositide 3-kinase (PI3K) inhibitor wortmannin. Consistently, I/R-induced increase of calpain activity and decrease of sarcoplasmic reticulum Ca(2+) ATPase (SERCA2) activity; and protein expression of SERCA2a, desmin, calpastatin and Akt was significantly attenuated by berbamine. In addition, I/R-decreased Akt protein was reversed by calpeptin. Moreover, berbamine further increased I/R-enhanced phosphorylation of Akt and glycogen synthase kinase-3β (GSK3β). These protections were abolished by wortmannin. Furthermore, berbamine significantly attenuated I/R-induced lactate dehydrogenase release, infarct size and contractile dysfunction, and such cardioprotective actions were abolished by wortmannin and 5-HD or mimicked by glycogen synthase kinase-3β (GSK3β) inhibitor SB216763 but without additive effect.


CONCLUSIONS
These findings suggest that berbamine confers cardioprotection against I/R injury by attenuating [Ca(2+)inf(i) overloading and preventing calpain activation through the activation of the PI3K-Akt-GSK3β pathway and, subsequently, opening of the mitoK(ATP) channel.
Key Laboratory of Stem Cell Biology and Laboratory of Molecular Cardiology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes of Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China.
Cai-Mei
CM
Zhang
Ling
L
Gao
Yan-Jun
YJ
Zheng
Huang-Tian
HT
Yang
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D044182:Benzylisoquinolines / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D000077191:Wortmannin
D000730:Androstadienes; D000889:Anti-Arrhythmia Agents; D044182:Benzylisoquinolines; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D009124:Muscle Proteins; D047428:Protein Kinase Inhibitors; C071482:calpeptin; D002154:Calpain; D002118:Calcium; C027870:berbamine; D000077191:Wortmannin