Dataset Information

Trans, trans-2,4-Decadienal, a lipid peroxidation product, induces inflammatory responses via Hsp90- or 14-3-3?-dependent mechanisms.

ABSTRACT: Peroxidation of polyunsaturated fatty acids leads to the formation of a large array of lipid-derived electrophiles (LDEs), many of which are important signaling molecules involved in the pathogenesis of human diseases. Previous research has shown that one of such LDEs, trans, trans-2,4-decadienal (tt-DDE), increases inflammation, however, the underlying mechanisms are not well understood. Here we used click chemistry-based proteomics to identify the cellular targets which are required for the pro-inflammatory effects of tt-DDE. We found that treatment with tt-DDE increased cytokine production, JNK phosphorylation, and activation of NF-?B signaling in macrophage cells, and increased severity of dextran sulfate sodium (DSS)-induced colonic inflammation in mice, demonstrating its pro-inflammatory effects in vitro and in vivo. Using click chemistry-based proteomics, we found that tt-DDE directly interacts with Hsp90 and 14-3-3?, which are two important proteins involved in inflammation and tumorigenesis. Furthermore, siRNA knockdown of Hsp90 or 14-3-3? abolished the pro-inflammatory effects of tt-DDE in macrophage cells. Together, our results support that tt-DDE increases inflammatory responses via Hsp90- and 14-3-3?-dependent mechanisms.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7003550 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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trans, trans-2,4-Decadienal, a lipid peroxidation product, induces inflammatory responses via Hsp90- or 14-3-3ζ-dependent mechanisms.

Wang Yuxin Y Dattmore Devon A DA Wang Weicang W Pohnert Georg G Wolfram Stefanie S Zhang Jianan J Yang Ran R Decker Eric A EA Lee Kin Sing Stephen KSS Zhang Guodong G

The Journal of nutritional biochemistry 20191113

Peroxidation of polyunsaturated fatty acids leads to the formation of a large array of lipid-derived electrophiles (LDEs), many of which are important signaling molecules involved in the pathogenesis of human diseases. Previous research has shown that one of such LDEs, trans, trans-2,4-decadienal (tt-DDE), increases inflammation, however, the underlying mechanisms are not well understood. Here we used click chemistry-based proteomics to identify the cellular targets which are required for the pr ...[more]

PMID: 31918337

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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 μM 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

Trans, trans-2,4-Decadienal, a lipid peroxidation product, induces inflammatory responses via Hsp90- or 14-3-3?-dependent mechanisms.

Publications

trans, trans-2,4-Decadienal, a lipid peroxidation product, induces inflammatory responses via Hsp90- or 14-3-3ζ-dependent mechanisms.

Similar Datasets

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