title: Danshen-Gegen decoction protects against hypoxia/reoxygenation-induced apoptosis by inhibiting mitochondrial permeability transition via the redox-sensitive ERK/Nrf2 and PKCε/mKATP pathways in H9c2 cardiomyocytes.
abstract: Danshen-Gegen (DG) Decoction, an herbal formulation containing Radix Salviae miltiorrhizae and Radix Puerariae lobatae, has been used for the treatment of coronary artery disease in Chinese medicine. In the present study, the involvement of ERK- and PKCε-mediated pathways in the cytoprotection against apoptosis afforded by DG pretreatment was investigated in H9c2 cardiomyocytes. Pretreatment with a methanol extract of aqueous DG decoction protected against hypoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes. The cytoprotection was associated the enhancement of cellular reduced glutathione and a reduced sensitivity to Ca(2+)-induced mitochondrial permeability transition. DG extract increased the production of cytochrome P-450 (CYP)-dependent reactive oxygen species (ROS) in H9c2 cardiomyocytes, which was accompanied by the concomitant activation of ERK1/2 and PKCε. The DG-induced ERK1/2 activation was followed by the translocation of Nrf2 from the cytosol to the mitochondria accompanied by an increase in the expression of glutathione-related antioxidant proteins. In addition, the increased expression of hemeoxygenase-1 was associated with the activation of Akt and BAD, indicative of anti-apoptotic activity. In conclusion, DG treatment activated both ERK/Nrf2 and PKCε pathways, presumably by ROS arising from CYP-catalyzed processes, with resultant inhibition of hypoxia/reoxygenation-induced apoptosis immediately after DG treatment or even after an extended time interval following DG treatment.
authors: Division of Life Science, The Hong Kong University of Science & Technology, Clear Water Bay, China.
authors: Po Yee
authors: PY
authors: Chiu
authors: Hoi Yan
authors: HY
authors: Leung
authors: Pou Kuan
authors: PK
authors: Leong
authors: Na
authors: N
authors: Chen
authors: Limin
authors: L
authors: Zhou
authors: Zhong
authors: Z
authors: Zuo
authors: Philip Y
authors: PY
authors: Lam
authors: Kam Ming
authors: KM
authors: Ko
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000737:chemistry; D015687:Cell Hypoxia; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D019610:Cytoprotection; D003600:Cytosol / Q000737:chemistry; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D000432:Methanol / Q000737:chemistry; D008929:Mitochondria, Heart / Q000737:chemistry* / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000187:drug effects*; D051267:NF-E2-Related Factor 2 / Q000737:chemistry; D010084:Oxidation-Reduction; D010539:Permeability; D051744:Protein Kinase C-epsilon / Q000737:chemistry; D021381:Protein Transport; D029908:Pueraria / Q000737:chemistry; D051381:Rats; D017382:Reactive Oxygen Species / Q000737:chemistry; D027561:Salvia miltiorrhiza / Q000737:chemistry
chemical_list: D000975:Antioxidants; C568783:Danshen-Gegen; D004365:Drugs, Chinese Herbal; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D017382:Reactive Oxygen Species; D003577:Cytochrome P-450 Enzyme System; C497257:Prkce protein, rat; D051744:Protein Kinase C-epsilon; D002118:Calcium; D000432:Methanol