TY - JOUR
T1 - Knockdown of Sestrin2 Increases Lipopolysaccharide-Induced Oxidative Stress, Apoptosis, and Fibrotic Reactions in H9c2 Cells and Heart Tissues of Mice via an AMPK-Dependent Mechanism
AU - Hwang, Hwan Jin
AU - Kim, Joo Won
AU - Chung, Hye Soo
AU - Seo, Ji A.
AU - Kim, Sin Gon
AU - Kim, Nan Hee
AU - Choi, Kyung Mook
AU - Baik, Sei Hyun
AU - Yoo, Hye Jin
N1 - Funding Information:
Dr. Hye Jin Yoo was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), which is funded by the Ministry of Education, Science and Technology (2015R1A1A1A05001173) and the Korean Diabetes Association (Hye Jin Yoo, 2017F-3).
PY - 2018
Y1 - 2018
N2 - Sestrin2 (sesn2) is an endogenous antioxidant protein that has recently gained attention for its potential to treat various inflammatory diseases. However, the relationship of sesn2 with cardiomyopathy is still unclear. In H9c2 cells, sesn2 knockdown reduced the level of 5′ adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, downregulated antioxidant genes including catalase and superoxide dismutase (SOD2), and increased reactive oxygen species (ROS) production upon lipopolysaccharide (LPS) treatment. LPS-mediated cell death and the expression of matrix metalloproteinase (MMP) 2 and MMP9 were significantly increased by sesn2 knockdown. However, these increases were prevented by treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator. Consistent with the in vitro results, AMPK phosphorylation was decreased in heart tissue from sesn2 knockdown mice compared to heart tissue from control C57BL/6 mice, which was associated with decreased expression of antioxidant genes and increased LPS-mediated cell death signaling. Furthermore, the decrease in AMPK phosphorylation caused by sesn2 knockdown increased LPS-mediated expression of cardiac fibrotic factors, including collagen type I and type III, in addition to MMP2 and MMP9, in heart tissue from C57BL/6 mice. These results suggest that sesn2 is a novel potential therapeutic target for cardiomyopathy under inflammatory conditions.
AB - Sestrin2 (sesn2) is an endogenous antioxidant protein that has recently gained attention for its potential to treat various inflammatory diseases. However, the relationship of sesn2 with cardiomyopathy is still unclear. In H9c2 cells, sesn2 knockdown reduced the level of 5′ adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, downregulated antioxidant genes including catalase and superoxide dismutase (SOD2), and increased reactive oxygen species (ROS) production upon lipopolysaccharide (LPS) treatment. LPS-mediated cell death and the expression of matrix metalloproteinase (MMP) 2 and MMP9 were significantly increased by sesn2 knockdown. However, these increases were prevented by treatment with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an AMPK activator. Consistent with the in vitro results, AMPK phosphorylation was decreased in heart tissue from sesn2 knockdown mice compared to heart tissue from control C57BL/6 mice, which was associated with decreased expression of antioxidant genes and increased LPS-mediated cell death signaling. Furthermore, the decrease in AMPK phosphorylation caused by sesn2 knockdown increased LPS-mediated expression of cardiac fibrotic factors, including collagen type I and type III, in addition to MMP2 and MMP9, in heart tissue from C57BL/6 mice. These results suggest that sesn2 is a novel potential therapeutic target for cardiomyopathy under inflammatory conditions.
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U2 - 10.1155/2018/6209140
DO - 10.1155/2018/6209140
M3 - Article
C2 - 30116150
AN - SCOPUS:85059365296
VL - 2018
JO - Mediators of Inflammation
JF - Mediators of Inflammation
SN - 0962-9351
M1 - 6209140
ER -