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.
Hwan-Jin HwangJoo Won KimHye Soo ChungJi A SeoSin Gon KimNan Hee KimKyung Mook ChoiSei Hyun BaikHye Jin YooPublished in: Mediators of inflammation (2018)
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.
Keyphrases
- protein kinase
- cell death
- cell cycle arrest
- anti inflammatory
- inflammatory response
- oxidative stress
- heart failure
- induced apoptosis
- poor prognosis
- high fat diet induced
- skeletal muscle
- reactive oxygen species
- pi k akt
- binding protein
- toll like receptor
- endoplasmic reticulum stress
- left ventricular
- type iii
- hydrogen peroxide
- idiopathic pulmonary fibrosis
- lps induced
- systemic sclerosis
- gene expression
- long non coding rna
- immune response
- dna damage
- signaling pathway
- metabolic syndrome
- risk assessment
- nitric oxide
- dna methylation
- cell proliferation
- climate change
- smoking cessation