Aberrant activation of p53-TRIB3 axis contributes to diabetic myocardial insulin resistance and sulforaphane protection.

Guangping Lu, Yufeng Tang, Ou Chen, Yuanfang Guo, Mengjie Xiao, Jie Wang, Qingbo Liu, Jiahao Li, Ting Gao, Xiaohui Zhang, Jingjing Zhang, Quanli Cheng, Rong Kuang, Junlian Gu
{"title":"Aberrant activation of p53-TRIB3 axis contributes to diabetic myocardial insulin resistance and sulforaphane protection.","authors":"Guangping Lu, Yufeng Tang, Ou Chen, Yuanfang Guo, Mengjie Xiao, Jie Wang, Qingbo Liu, Jiahao Li, Ting Gao, Xiaohui Zhang, Jingjing Zhang, Quanli Cheng, Rong Kuang, Junlian Gu","doi":"10.1016/j.jare.2024.07.025","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Insulin resistance (IR) is associated with multiple pathological features. Although p53- or TRIB3-orchestrated IR is extensively studied in adipose tissue and liver, the role of p53-TRIB3 axis in myocardial IR remains unknown, and more importantly target-directed therapies of myocardial IR are missing.</p><p><strong>Objectives: </strong>Considering the beneficial effects of sulforaphane (SFN) on cardiovascular health, it is of particular interest to explore whether SFN protects against myocardial IR with a focus on the regulatory role of p53-TRIB3 axis.</p><p><strong>Methods: </strong>Mouse models including cardiac specific p53-overexpressing transgenic (p53-cTg) mice and Trib3 knockout (Trib3-KO) mice, combined with primary cardiomyocytes treated with p53 activator (nutlin-3a) and inhibitor (pifithrin-α, PFT-α), or transfected with p53-shRNA and Trib3-shRNA, followed by multiple molecular biological methodologies, were used to investigate the role of p53-TRIB3 axis in SFN actions on myocardial IR.</p><p><strong>Results: </strong>Here, we report that knockdown of p53 rescued cardiac insulin-stimulated AKT phosphorylation, while up-regulation of p53 by nutlin-3a or p53-cTg mice blunted insulin sensitivity in cardiomyocytes under diabetic conditions. Diabetic attenuation of AKT-mediated cardiac insulin signaling was markedly reversed by SFN in p53-Tg<sup>fl/fl</sup> mice, but not in p53-cTg mice. Importantly, we identified TRIB3 was elevated in p53-cTg diabetic mice, and confirmed the physical interaction between p53 and TRIB3. Trib3-KO diabetic mice displayed improved insulin sensitivity in the heart. More specifically, the AMPKα-triggered CHOP phosphorylation and degradation were essential for p53 on the transcriptional regulation of Trib3.</p><p><strong>Conclusion: </strong>Overall, these results indicate that inhibiting the p53-TRIB3 pathway by SFN plays an unsuspected key role in the improvement of myocardial IR, which may be a promising strategy for attenuating diabetic cardiomyopathy (DCM) in diabetic patients.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of advanced research","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.jare.2024.07.025","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

Introduction: Insulin resistance (IR) is associated with multiple pathological features. Although p53- or TRIB3-orchestrated IR is extensively studied in adipose tissue and liver, the role of p53-TRIB3 axis in myocardial IR remains unknown, and more importantly target-directed therapies of myocardial IR are missing.

Objectives: Considering the beneficial effects of sulforaphane (SFN) on cardiovascular health, it is of particular interest to explore whether SFN protects against myocardial IR with a focus on the regulatory role of p53-TRIB3 axis.

Methods: Mouse models including cardiac specific p53-overexpressing transgenic (p53-cTg) mice and Trib3 knockout (Trib3-KO) mice, combined with primary cardiomyocytes treated with p53 activator (nutlin-3a) and inhibitor (pifithrin-α, PFT-α), or transfected with p53-shRNA and Trib3-shRNA, followed by multiple molecular biological methodologies, were used to investigate the role of p53-TRIB3 axis in SFN actions on myocardial IR.

Results: Here, we report that knockdown of p53 rescued cardiac insulin-stimulated AKT phosphorylation, while up-regulation of p53 by nutlin-3a or p53-cTg mice blunted insulin sensitivity in cardiomyocytes under diabetic conditions. Diabetic attenuation of AKT-mediated cardiac insulin signaling was markedly reversed by SFN in p53-Tgfl/fl mice, but not in p53-cTg mice. Importantly, we identified TRIB3 was elevated in p53-cTg diabetic mice, and confirmed the physical interaction between p53 and TRIB3. Trib3-KO diabetic mice displayed improved insulin sensitivity in the heart. More specifically, the AMPKα-triggered CHOP phosphorylation and degradation were essential for p53 on the transcriptional regulation of Trib3.

Conclusion: Overall, these results indicate that inhibiting the p53-TRIB3 pathway by SFN plays an unsuspected key role in the improvement of myocardial IR, which may be a promising strategy for attenuating diabetic cardiomyopathy (DCM) in diabetic patients.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
p53-TRIB3轴的异常激活导致糖尿病心肌胰岛素抵抗和舒乐安定保护。
导言胰岛素抵抗(IR)与多种病理特征相关。虽然p53或TRIB3协调的IR在脂肪组织和肝脏中得到了广泛的研究,但p53-TRIB3轴在心肌IR中的作用仍然未知,更重要的是,心肌IR的靶向疗法尚缺:考虑到莱菔硫烷(SFN)对心血管健康的有益影响,探讨莱菔硫烷是否能保护心肌IR,重点关注p53-TRIB3轴的调节作用,是一项特别有意义的研究:方法:采用心脏特异性 p53 高表达转基因(p53-cTg)小鼠和 Trib3 基因敲除(Trib3-KO)小鼠等小鼠模型,结合经 p53 激活剂(nutlin-3a)和抑制剂(pifithrin-α,PFT-α)处理或转染 p53-shRNA 和 Trib3-shRNA 的原代心肌细胞,并采用多种分子生物学方法,研究 p53-TRIB3 轴在 SFN 对心肌 IR 作用中的作用:结果:在此,我们报告了p53的敲除可挽救胰岛素刺激的心肌AKT磷酸化,而通过nutlin-3a或p53-cTg小鼠上调p53可减弱糖尿病条件下心肌细胞的胰岛素敏感性。在p53-Tgfl/fl小鼠中,SFN能明显逆转糖尿病对AKT介导的心脏胰岛素信号转导的削弱,但在p53-cTg小鼠中却不能。重要的是,我们发现在p53-cTg糖尿病小鼠中TRIB3升高,并证实了p53和TRIB3之间的物理相互作用。Trib3-KO 糖尿病小鼠的心脏对胰岛素的敏感性得到改善。更具体地说,AMPKα触发的CHOP磷酸化和降解对p53调控Trib3的转录至关重要:总之,这些结果表明,SFN抑制p53-TRIB3通路在改善心肌IR方面发挥了未被察觉的关键作用,这可能是减轻糖尿病患者糖尿病心肌病(DCM)的一种有前途的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
自引率
0.00%
发文量
0
期刊最新文献
Transient receptor potential channels in viral infectious diseases: Biological characteristics and regulatory mechanisms. Integrated stress response activation induced by usnic acid alleviates BCL-2 inhibitor ABT-199 resistance in acute myeloid leukemia. Pharmacological upregulation of macrophage-derived itaconic acid by pubescenoside C attenuated myocardial ischemia-reperfusion injury. Population genomics analyses reveal the role of hybridization in the rapid invasion of fall armyworm. Gastrodin attenuates high fructose-induced sweet taste preference decrease by inhibiting hippocampal neural stem cell ferroptosis.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1