Sestrin2 modulates cardiac inflammatory response through maintaining redox homeostasis during ischemia and reperfusion

Ren, Di; Quan, Nanhu; Fedorova, Julia; Zhang, Jingwen; He, Zhibin; Li, Ji

doi:10.1016/j.redox.2020.101556

Cited by 33 publications

(37 citation statements)

References 46 publications

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“…Sesn2 was demonstrated to regulate AMPK and mTORC1 signaling pathway under various stress conditions, such as oxidative stress and ischemic stress, which are critical for mediating cellular energetic, metabolic, and translational process [ 11 , 15 , 16 ]. To explore the roles of Sesn2 as an age-related regulator in adaptation to I/R stress, RNA-Seq was performed to assess the gene expression alteration pattern in myocardium under cardiac I/R stress in young-WT, aged-WT and Sesn2 KO mice.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, our lab reported that Sesn2 is a signaling regulator which is critical for AMPK activation by increasing its association with LKB1 as a scaffold protein in cytoplasm [ 13 ]. Furthermore, our lab also reported that Sesn2 modulate mitochondrial biosynthesis through PGC1-α signaling and affect myocardium apoptosis in the post-myocardium infarction model [ 16 ]. The comprehensive roles and mechanisms of Sesn2 require further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Young C57BL/6J mice (3–6 months, young-WT), Aged-WT C57BL/6 J mice (24–26 months, aged-WT) were provided by National Institute on Aging (NIA), the Sesn2 knockout (Sesn2 KO) (3–6 months, C57BL/6 J background), and its littermate mice were bred in our laboratory [ 13 , 16 , 17 ]. Cardiomyocyte specific deletion of Sesn2 gene was generated by breeding Sesn2 flox/flox mice (3–6 months, C57BL/6 J background) with transgenic mice that carried an autosomally integrated Cre gene driven by the cardiac-specific alpha-myosin heavy chain promoter (αMHC) (Jackson Laboratory, 018,972) in our laboratory.…”

Section: Methodsmentioning

confidence: 99%

“…In mice, we reported that Sesn2 expression decreases in the aging heart leading to intolerance to ischemia reperfusion (I/R) stress [ 15 ]. Furthermore, the rescue of Sesn2 in aged heart improves cardiac performance during I/R, indicating Sesn2 is an age-related cardioprotective effector and a new therapeutic target in cardiovascular disease for the aging population [ 12 , 15 , 16 ]. However, the comprehensive mechanisms by which Sesn2 protects the heart, especially aged heart, from I/R injury remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Sestrin2 maintains OXPHOS integrity to modulate cardiac substrate metabolism during ischemia and reperfusion

Ren

Fedorova

et al. 2021

Redox Biology

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Sestrin2 (Sesn2) is a stress-inducible protein that declines with aging in the heart. We reported that rescue Sesn2 levels in aged mouse hearts through gene therapy improves the resistance of aged hearts to ischemia and reperfusion (I/R) insults. We hypothesize that Sesn2 as a scaffold protein maintains mitochondrial integrity to protect heart from ischemic injury during I/R. Young C57BL/6 J (3–6 months), aged C57BL/6 J (24–26 months), and young Sesn2 KO (3–6 months, C57BL/6 J background) mice were subjected to in vivo regional ischemia and reperfusion. The left ventricle was collected for transcriptomics, proteomics and metabolomics analysis. The results demonstrated that Sesn2 deficiency leads to aging-like cardiac diastolic dysfunction and intolerance to ischemia reperfusion stress. Seahorse analysis demonstrated that Sesn2 deficiency in aged and young Sesn2 KO versus young hearts lead to impaired mitochondrial respiration rate with defects in Complex I and Complex II activity. The Sesn2 targeted proteomics analysis revealed that Sesn2 plays a critical role in maintaining mitochondrial functional integrity through modulating mitochondria biosynthesis and assembling of oxidative phosphorylation (OXPHOS) complexes. The RNA-Seq data showed that alterations in the expression of mitochondrial compositional and functional genes and substrate metabolism related genes in young Sesn2 KO and aged versus young hearts. Further immunofluorescence and immunoprecipitation analysis demonstrated that Sesn2 is translocated into mitochondria and interacts with OXPHOS components to maintain mitochondrial integrity in response to I/R stress. Biochemical analysis revealed that Sesn2 is associated with citrate cycle components to modulate pyruvate dehydrogenase and isocitrate dehydrogenase activities during I/R stress. Thus, Sesn2 serves as a scaffold protein interacting with OXPHOS components to maintain mitochondrial integrity under I/R stress. Age-related downregulation of cardiac Sesn2 fragilizes mitochondrial functional integrity in response to ischemic stress.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sestrin2 maintains OXPHOS integrity to modulate cardiac substrate metabolism during ischemia and reperfusion

Ren

Fedorova

et al. 2021

Redox Biology

Self Cite

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“…These findings suggest that (1) sestrin2 is a scaffold protein that mediates the activation of AMPK in ischemic myocardium, and (2) decreased sestrin2 levels in aging led to blunted ischemic AMPK activation and increased the sensitivity to ischemic insults. In addition, the sestrin2 knockout mice showed an aged-like phenotype in their hearts with excessive oxidative stress, disorganized myocardium, and transcriptomic alterations with I/R stress similar to aged mice [ 45 ]. Sestrin2 deficiency increased oxidative stress with up-regulated proinflammatory signaling and greater myocardial damage after I/R stress.…”

Section: Sestrin2 and Cardiac Diseasesmentioning

confidence: 99%

The Protective Role of Sestrin2 in Atherosclerotic and Cardiac Diseases

Kishimoto

Kondo

Momiyama

2021

IJMS

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Atherosclerotic disease, such as coronary artery disease (CAD), is known to be a chronic inflammatory disease, as well as an age-related disease. Excessive oxidative stress produced by reactive oxygen species (ROS) contributes to the pathogenesis of atherosclerosis. Sestrin2 is an anti-oxidant protein that is induced by various stresses such as hypoxia, DNA damage, and oxidative stress. Sestrin2 is also suggested to be associated with aging. Sestrin2 is expressed and secreted mainly by macrophages, endothelial cells, and cardiomyocytes. Sestrin2 plays an important role in suppressing the production and accumulation of ROS, thus protecting cells from oxidative damage. Since sestrin2 is reported to have anti-oxidant and anti-inflammatory properties, it may play a protective role against the progression of atherosclerosis and may be a potential therapeutic target for the amelioration of atherosclerosis. Regarding the association between blood sestrin2 levels and atherosclerotic disease, the blood sestrin2 levels in patients with CAD or carotid atherosclerosis were reported to be high. High blood sestrin2 levels in patients with such atherosclerotic disease may reflect a compensatory response to increased oxidative stress and may help protect against the progression of atherosclerosis. This review describes the protective role of sestrin2 against the progression of atherosclerotic and cardiac diseases.

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