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Investigating the role and mechanism of stress induced protein Sesn2 in aged-related adaptive response to cardiac ischemia reperfusion injury

ABSTRACT: Purpose: to reveal the myocardium transcriptomic profile shift pattern before/after Ischemia Reperfusion stress in young, aged, and Sesn2-knockout mice. The goals of this study are to compare the transcriptomic shift pattern among young, aged, and Sesn2-knockout to explore the caridoprotective mechanism of Sesn2 in Ischemia Reperfusion stress and the critical roles of Sesn2 in age-related adapting response to Ischemia Reperfusion stress. Methods: Myocardium transcriptome profiles of young (3-4 months) wild-type, aged (24-26 months) wild-type, and Sesn2-knockout (3-4 months) mice in normal physiological and Ischemia Reperfusion stressed conditions. Results: Sesn2 is critical to repress inflammation and maintain metabolic and mitochondria homeostasis in hearts under Ischemia Reperfusion stress, especially to aged hearts.

ORGANISM(S): Mus musculus

PROVIDER: GSE130217 | GEO | 2020/06/01

REPOSITORIES: GEO

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Project description:Coronary heart disease is the leading cause of death worldwide. After an acute myocardial infarction, early reperfusion reduces infarct size, which correlates with improved clinical outcomes. Paradoxically, reperfusion although relieving ischemia, accelerates apoptosis in injured cardiomyocytes, which has led to the view that myocardial salvage is futile beyond the first few hours of reperfusion. In murine hearts subjected to 90 min of coronary artery occlusion and then 48 h of reperfusion, we show transient activation of intrinsic prosurvival insulin-like growth factor-1 (IGF-1) signaling. In these hearts, acute IGF-1 receptor inhibition decreases the abundance of prosurvival signaling molecules, and markedly activates caspase-3, a potent effector of apoptosis, in infarct border zone cardiomyocytes. We found that mouse mast cell protease-4 (MMCP-4) degraded IGF-1 in vitro by a novel catalytic activity of chymases. In vivo, this degradation, which is triggered by mast cell infiltration into the peri-infarct region and MMCP-4 extravasation, between 48 and 72 h post-ischemia/reperfusion (I/R), attenuates IGF-1 prosurvival signaling. In MMCP-4-deficient mice, while infarct size is not reduced at 24 h post-I/R, at 72 h post-I/R myocardial IGF-1 levels and signaling are increased, resulting in activation of the survival kinases Akt and ERK, inhibition of caspase-3, and reduced myocardial cell death. As a consequence, I/R-mediated loss of viable myocardium, adverse cardiac remodeling and contractile impairment are markedly reduced. Cardiomyocyte survival with consequent myocardial salvage may thus be possible even days after an ischemic insult, making them a novel therapeutic target for delayed cardioprotective therapy. Group 1 is wild type C57Bl6 uninjured hearts. These mice were not undergone any surgery and used as controls. Group 2 are wild type C57Bl6 72 h post-ischemia reperfusion (IR) injury hearts. These mice for subjected to ischemia reperfusion (IR) involving 90 min of left anterior descending coronary artery occlusion followed by reperfusion for 3 days or 72 h.

Project description:Background: Demographic studies have shown that the mean age of patients requiring coronary artery bypass surgery (CABG) is 68 years with approximately 44% of these patients being female . In recent studies, women have been shown to have a significantly greater operative risk as compared to men and that women have worse outcomes after cardiac surgery. Recently we have shown that cardioprotection afforded by cardioplegia is modulated by RNA and protein dependent mechanisms and is significantly decreased with age and in particular is significantly decreased in the aged female. Methods: The mechanisms through which cardioplegia affords cardioprotection are complex and can not be investigated as a single entity but rather must be investigated using a systems approach. To meet these needs we have used microarray and proteomic analysis. The combined use of these two techniques allows for the identification of functionally related gene groups and protein biomarkers. Mature 15 to 20 weeks; 3 to 4 kg) and aged (not senescent, >32 months; 5 to 6 kg) male and female New Zealand White rabbits were used for in situ blood perfused cardiopulmonary bypass. Control hearts received 30 minutes sham ischemia and 120 minutes sham reperfusion. Global ischemia (GI) hearts received 30 minutes of global ischemia. GI was achieved by crossclamping of the aorta. Cardioplegia hearts received cold blood cardioplegia (Deaconess Surgical Associates (DSA) solution (containing 50 uM diazoxide) prior to GI. Following 30 minutes of GI the crossclamp was released, the cardiopulmonary bypass was ceased and the hearts were reperfused for 120 minutes. The hearts were removed flushed of blood and then quick frozen in liquid nitrogen prior to isolation of RNA and protein. Microarray and high throughput proteomic analysis was performed as previously described. Results: Our studies demonstrate that the cardioprotection afforded by cardioplegia is modulated by RNA and protein dependent mechanisms. Our data also show that there are significant differences in the proteins expressed in the mature and aged. Principal component analysis indicated that in the mature male, mature female, and aged male the proteins expressed in control, global ischemia, and cardioplegia were diverse and clustered for individual treatments suggesting that the proteins had different expression levels in each treatment. In contrast, in the aged female the proteins expressed in global ischemia and in cardioplegia were clustered together, suggesting there was no difference in the proteins expressed during global ischemia and with cardioplegia. Glycolysis/gluconeogensis was a significant functional pathway for the aged male but not the mature male or female. Glycolytic and gluconeogenic proteins were significantly up-regulated in the aged male compared to the female and significantly up-regulated in the aged male with cardioplegia as compared to global ischemia. In the aged female 9 unique mitochondrial proteins were up-regulated with cardioplegia. These proteins were associated with oxidative phosphorylation, the electron transport chain, the formation of pyruvate, and the tricarboxylic acid (TCA) cycle, but not glycolysis nor gluconeogenesis. Conclusions: Our study demonstrates that the mitochondrion plays a key role in age and gender specific cardioprotection. The identification of these specific pathways and biomarkers should allow for the development of age and gender specific cardioprotection and significantly decrease morbidity and mortality in the aged female. Rabbit heart (atria and ventricles):control vs. global ischemia; control vs. cardioplegia; cardioplegia vs. global ischemia

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Investigating the role and mechanism of stress induced protein Sesn2 in aged-related adaptive response to cardiac ischemia reperfusion injury

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