Antiapoptotic Effect of Novel Compound from Herba leonuri-Leonurine (SCM-198): A Mechanism Through Inhibition of Mitochondria Dysfunction in H9c2 Cells

Xin      Hua Liu; Li      Long Pan; Qi      Hai Gong; Yi      Zhun Zhu

doi:10.2174/138920110793262015

Abstract

Apoptosis of cardiomyocytes induced by oxidative stress play a critical role in cardiac dysfunction associated with ventricular remodeling and heart failure. We recently reported that leonurine attenuated hypoxia-induced cardiomyocyte damage. In this study, we investigated the mechanism of leonurine (originally from Herba leonuri but we synthesized it chemically, it as also called SCM-198) in protecting hydrogen peroxide (H2O2)-induced rat embryonic heart-derived H9c2 cells from apoptosis. Exposing H9c2 cells to H2O2 significantly decreased cell viability, and this was attenuated by pretreatment with leonurine for 4 h in a concentration-dependent manner. Meanwhile, leonurine was found to reduce intracellular reactive oxygen species (ROS) generation in H2O2-stimulated cell. Moreover, H9c2 cells stimulated by H2O2 was accompanied with apparent apoptotic characteristics, including fragmentation of DNA, apoptotic body formation, release of cytochrome c, translocation of Bax to mitochondria, loss of mitochondrial membrane potential (Δψm) and activation of caspase 3. Furthermore, H2O2 also induced rapid and significant phosphorylation of the c-Jun-N-terminal kinase 1/2 (JNK1/2), which was inhibited SP600125 (a JNK1/2 inhibitor). All of these events were attenuated by leonurine pretreatment. Taken together, these results demonstrated that leonurine could protect H9c2 cells from H2O2-induced apoptosis via modulation of mitochondrial dysfunction associated with blocking the activation of JNK1/2.

Keywords: Leonurine, hydrogen peroxide, mitochondria, cytochrome c, reactive oxygen species, c-Jun N-terminal kinase 1/2, cardiomyocytes, fragmentation of DNA, autoimmune, neurodegenerative, chromatin, oxidative stress, hyperosmolality, chemotherapeutic drugs, mitochondrial membrane, permeability transition pore (PTP), dysmenorrhea, antiapoptotic activity, c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase (MAPK), fetal bovine serum (FBS), streptomycin, electrophoresis, electrophoresis-electrochemical detection (CE-ECD), Tris-buffered saline (TBST), DNA-agarose gel electrophoresis, immunoblotting, phosphorylation, cytotoxic effects, myocardial apoptosis, necrosis, hosphorylation