Aberrant activation of p53-TRIB3 axis contributes to diabetic myocardial insulin resistance and sulforaphane protection,Journal of Advanced Research

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Aberrant activation of p53-TRIB3 axis contributes to diabetic myocardial insulin resistance and sulforaphane protection
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2024-07-26 , DOI: 10.1016/j.jare.2024.07.025
Guangping Lu ₁ , Yufeng Tang ₂ , Ou Chen ₁ , Yuanfang Guo ₁ , Mengjie Xiao ₁ , Jie Wang ₁ , Qingbo Liu ₁ , Jiahao Li ₁ , Ting Gao ₁ , Xiaohui Zhang ₁ , Jingjing Zhang ₃ , Quanli Cheng ₄ , Rong Kuang ₅ , Junlian Gu ₁

Affiliation

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-Tg^fl/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.

中文翻译：

p53-TRIB3 轴的异常激活有助于糖尿病心肌胰岛素抵抗和萝卜硫素保护

介绍

胰岛素抵抗（IR）与多种病理特征有关。尽管 p53 或 TRIB3 编排的 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 的靶向治疗缺失。

目标

考虑到萝卜硫素（SFN）对心血管健康的有益影响，探索 SFN 是否能防止心肌 IR 特别有趣，重点是 p53-TRIB3 轴的调节作用。

方法

小鼠模型包括心脏特异性 p53 过表达转基因（p53-cTg）小鼠和 Trib3 敲除（Trib3-KO）小鼠，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，然后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

在这里，我们报道了 p53 的敲除挽救了心脏胰岛素刺激的 AKT 磷酸化，而 nutlin-3a 或 p53-cTg 小鼠对 p53 的上调减弱了糖尿病条件下心肌细胞的胰岛素敏感性。在 p53-Tg ^fl/fl 小鼠中，SFN 显着逆转了 AKT 介导的心脏胰岛素信号传导的糖尿病减弱，但在 p53-cTg 小鼠中则没有。重要的是，我们发现 TRIB3 在 p53-cTg 糖尿病小鼠中升高，并证实了 p53 和 TRIB3 之间的物理相互作用。Trib3-KO 糖尿病小鼠心脏中胰岛素敏感性有所改善。更具体地说，AMPKα 触发的 CHOP 磷酸化和降解对 p53 对 Trib3 的转录调节至关重要。