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Dual pathways of p53 mediated glucolipotoxicity-induced apoptosis of rat cardiomyoblast cell: activation of p53 proapoptosis and inhibition of Nrf2-NQO1 antiapoptosis

Authors
Wang, HJ; Lee, EY; Han, SJ; Kim, SH; Lee, BW; Ahn, CW; Cha, BS; Lee, HC
Citation
Metabolism: clinical and experimental, 61(4):496-503, 2012
Journal Title
Metabolism: clinical and experimental
ISSN
0026-04951532-8600
Abstract
Reactive oxygen species (ROS), driven by excessive levels of glucose and free fatty acids, appears to induce cell apoptosis. However, the underlying molecular mechanism of this process remains unclear in cardiac myocytes. We investigated the glucolipotoxicity effects of high glucose and palmitic acid (C16:0) on the rat cardiomyoblast cell line (H9c2) focusing on tumor suppressor p53. Cultured H9c2 rat cardiomyoblasts were exposed to palmitate and /or to an elevated glucose concentration for 18 hours. Only the glucolipotoxic condition of 30 mM glucose in combination with 250 μM palmitate resulted in significant generation of ROS and upregulation of p53 which caused to an increased cleavage of caspase-3. On the other hand, the expression of NF-E2-related factor 2 (Nrf2) showed increased tendency while the expression of NAD(P)H: quinone oxidoreductase-1 (NQO1) was decreased. N-acetyl L cysteins and pifithrin-α, an inhibitor of p53 abrogated glucolipotoxicity-induced ROS generation and p53 expression. Chromatin immunoprecipitation analysis revealed that p53 interacted antioxidant responsive elements (ARE)-containing promoter of NQO1. Upregulated p53 counteracted the Nrf2-induced transcription of ARE-containing promoter of NQO1 gene and leaded to decrease in NQO1 expression. We demonstrated that the elevated p53 mediated glucolipotoxicity-induced apoptosis of rat cardiomyoblast cell through dual pathways: stimulating pro-apoptosis signaling as well as suppressing anti-apoptosis pathway of Nrf2-NQO1 signaling.
MeSH terms
Acetylcysteine/pharmacologyAnimalsApoptosis/*physiologyBenzothiazoles/pharmacologyCell LineFree Radical Scavengers/pharmacologyGlucose/*metabolismMyocytes, Cardiac/*metabolismNAD(P)H Dehydrogenase (Quinone)/antagonists & inhibitors/*metabolismNF-E2-Related Factor 2/*metabolismPalmitic Acid/*metabolismRNA, Small Interfering/pharmacologyRatsReactive Oxygen Species/antagonists & inhibitors/*metabolismToluene/analogs & derivatives/pharmacologyTumor Suppressor Protein p53/antagonists & inhibitors/*metabolism
DOI
10.1016/j.metabol.2011.09.005
PMID
22154326
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Endocrinology & Metabolism
AJOU Authors
한, 승진
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