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Mesenchymal stem cells in alleviating sepsis-induced mice cardiac dysfunction via inhibition of mTORC1-p70S6K signal pathway.

ABSTRACT: Sepsis-induced cardiac dysfunction remains a major cause of morbidity and mortality in patients suffered from severe trauma. Mesenchymal stem cells (MSCs) -based treatment has been verified as a promising approach to mitigate the sepsis-induced cardiac dysfunction, but the mechanism is still ambiguous. Thus, our study was designed to explore the potential role of MSCs in sepsis-induced cardiac dysfunction. In vivo bioluminescence imaging revealed 80% acute donor cell death of bone marrow-derived MSCs (BM-MSCs) within 3 days after transplantation. However, echocardiography demonstrated that systolic function in wild-type mice group were reduced after sepsis, while the cardiac function was relatively well persevered in cardiac-conditional deletion of Raptor (component of mTORC1 complex) mice group. Raptor KO group treated with BM-MSCs appeared better cardiac function than other groups (P<0.05). In vitro cell study revealed that co-culture of H9C2 (Raptor-Knock down) and BM-MSC could attenuate the level of proinflammatory cytokines and promote the expression of anti-inflammatory cytokine accompanied by mTORC2-Akt activation (P<0.05). In contrast, co-culture H9C2 (Raptor-O.E) and BM-MSC could aggravate the inflammatory response accompanied by the activation of mTORC1-p70S6K and inhibition of mTORC2-Akt (P<0.05). The immunomodulatory property of MSC is related to the inhibition of mTORC1-p70S6K and activation of mTORC2-Akt signaling pathway. mTORC1-p70S6K and mTORC2-Akt pathways were involved in the therapeutic adjuncts of MSC. The possible mechanism due to MSC`s immunomodulatory property through activation of mTORC2-Akt and inhibition of mTORC1-p70S6K signal pathways which may lead to modulate the expression of inflammation cytokines.

SUBMITTER: Huang W

PROVIDER: S-EPMC5327616 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Mesenchymal stem cells in alleviating sepsis-induced mice cardiac dysfunction via inhibition of mTORC1-p70S6K signal pathway.

Huang Wei W Fan Wensi W Wang Yabin Y Han Dong D Li Xiujuan X Li Shuang S Li Congye C Xu Bin B Huang Yuesheng Y Fu Xiaobin X Cao Feng F

Cell death discovery 20170227

Sepsis-induced cardiac dysfunction remains a major cause of morbidity and mortality in patients suffered from severe trauma. Mesenchymal stem cells (MSCs) -based treatment has been verified as a promising approach to mitigate the sepsis-induced cardiac dysfunction, but the mechanism is still ambiguous. Thus, our study was designed to explore the potential role of MSCs in sepsis-induced cardiac dysfunction. <i>In vivo</i> bioluminescence imaging revealed 80% acute donor cell death of bone marrow- ...[more]

PMID: 28250969

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Project description:Reactive oxygen species (ROS) are elevated in the heart in response to hemodynamic and metabolic stress and promote hypertrophic signaling. ROS also mediate the formation of lipid peroxidation-derived aldehydes that may promote myocardial hypertrophy. One lipid peroxidation by-product, 4-hydroxy-trans-2-nonenal (HNE), is a reactive aldehyde that covalently modifies proteins thereby altering their function. HNE adducts directly inhibit the activity of LKB1, a serine/threonine kinase involved in regulating cellular growth in part through its interaction with the AMP-activated protein kinase (AMPK), but whether this drives myocardial growth is unclear. We tested the hypothesis that HNE promotes myocardial protein synthesis and if this effect is associated with impaired LKB1-AMPK signaling. In adult rat ventricular cardiomyocytes, exposure to HNE (10 ?M for 1h) caused HNE-LKB1 adduct formation and inhibited LKB1 activity. HNE inhibited the downstream kinase AMPK, increased hypertrophic mTOR-p70S6K-RPS6 signaling, and stimulated protein synthesis by 27.1 ± 3.5%. HNE also stimulated Erk1/2 signaling, which contributed to RPS6 activation but was not required for HNE-stimulated protein synthesis. HNE-stimulated RPS6 phosphorylation was completely blocked using the mTOR inhibitor rapamycin. To evaluate if LKB1 inhibition by itself could promote the hypertrophic signaling changes observed with HNE, LKB1 was depleted in adult rat ventricular myocytes using siRNA. LKB1 knockdown did not replicate the effect of HNE on hypertrophic signaling or affect HNE-stimulated RPS6 phosphorylation. Thus, in adult cardiac myocytes HNE stimulates protein synthesis by activation of mTORC1-p70S6K-RPS6 signaling most likely mediated by direct inhibition of AMPK. Because HNE in the myocardium is commonly increased by stimuli that cause pathologic hypertrophy, these findings suggest that therapies that prevent activation of mTORC1-p70S6K-RPS6 signaling may be of therapeutic value.

Dataset Information

Mesenchymal stem cells in alleviating sepsis-induced mice cardiac dysfunction via inhibition of mTORC1-p70S6K signal pathway.

Publications

Mesenchymal stem cells in alleviating sepsis-induced mice cardiac dysfunction via inhibition of mTORC1-p70S6K signal pathway.

Similar Datasets

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