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Isorhamnetin inhibits H 2 O 2 ‐induced activation of the intrinsic apoptotic pathway in H9c2 cardiomyocytes through scavenging reactive oxygen species and ERK inactivation
Author(s) -
Sun Bing,
Sun GuiBo,
Xiao Jing,
Chen RongChang,
Wang Xin,
Wu Ying,
Cao Li,
Yang ZhiHong,
Sun XiaoBo
Publication year - 2012
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.23371
Subject(s) - isorhamnetin , mapk/erk pathway , reactive oxygen species , apoptosis , microbiology and biotechnology , chemistry , signal transduction , downregulation and upregulation , biochemistry , biology , antioxidant , gene , kaempferol , quercetin
Abstract As a traditional Chinese medicine, the sea buckthorn ( Hippophae rhamnoides L.) has a long history in the treatment of ischemic heart disease and circulatory disorders. However, the active compounds responsible for and the underlying mechanisms of these effects are not fully understood. In this article, isorhamnetin pretreatment counteracted H 2 O 2 ‐induced apoptotic damage in H9c2 cardiomyocytes. Isorhamnetin did not inhibit the death receptor‐dependent or extrinsic apoptotic pathways, as characterized by its absence in both caspase‐8 inactivation and tBid downregulation along with unchanged Fas and TNFR1 mRNA levels. Instead, isorhamnetin specifically suppressed the mitochondria‐dependent or intrinsic apoptotic pathways, as characterized by inactivation of caspase‐9 and ‐3, maintenance of the mitochondrial membrane potential (ΔΨm), and regulation of a series of Bcl‐2 family genes upstream of ΔΨm. The anti‐apoptotic effects of isorhamnetin were linked to decreased ROS generation. H 2 O 2 activated ERK and p53, whereas isorhamnetin inhibited their activation. ERK overexpression overrode the isorhamnetin‐induced inhibition of the intrinsic apoptotic pathway in H9c2 cardiomyocytes, which indicated that an ERK‐dependent pathway was involved. Furthermore, N ‐acetyl cysteine (a potent ROS scavenger) could attenuate the H 2 O 2 ‐induced apoptosis. However, PD98059 (an ERK‐specific inhibitor) could not effectively antagonize ROS generation, which indicates that ROS may be an upstream inducer of ERK. In conclusion, isorhamnetin inhibits the H 2 O 2 ‐induced activation of the intrinsic apoptotic pathway via ROS scavenging and ERK inactivation. Therefore, isorhamnetin is a promising reagent for the treatment of ROS‐induced cardiomyopathy. J. Cell. Biochem. 113: 473–485, 2012. © 2011 Wiley Periodicals, Inc.