Berbamine protects the heart from ischemia/reperfusion injury by maintaining cytosolic Ca(2+) homeostasis and preventing calpain activation

• Published in: Circulation journal : official journal of the Japanese Circulation Society Vol. 76; no. 8; pp. 1993 - 2002
• Main Authors: Zhang, Cai-Mei, Gao, Ling, Zheng, Yan-Jun, Yang, Huang-Tian
• Format: Journal Article
• Language: English
• Published: Japan 2012
• Subjects: Androstadienes - pharmacology; Animals; Anti-Arrhythmia Agents - pharmacology; Benzylisoquinolines - pharmacology; Calcium - metabolism; Calpain - metabolism; Cells, Cultured; Cysteine Proteinase Inhibitors - pharmacology; Dipeptides - pharmacology; Enzyme Activation - drug effects; Male; Muscle Proteins - antagonists & inhibitors; Muscle Proteins - metabolism; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - prevention & control; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Wortmannin
• ISSN: 1347-4820
• DOI: 10.1253/circj.CJ-11-1431

Berbamine, a natural compound from Barberry, was reported to protect myocardium from ischemia/reperfusion (I/R) injury, but the underlying mechanisms are largely unknown. 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. 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.