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

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

  • J Adv Res. 2024 Jul 26:S2090-1232(24)00307-2. 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 6
Affiliations

Affiliations

  • 1 School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 2 Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, China.
  • 3 Department of Cardiology at the First Hospital of China Medical University, and Department of Cardiology at the People's Hospital of Liaoning Province, Shenyang, Liaoning 110016, China.
  • 4 Department of Cardiovascular Disease, First Hospital of Jilin University, Changchun, Jilin 130021, China. Electronic address: quanlicheng0412@jlu.edu.cn.
  • 5 NMPA Key Laboratory for Animal Alternative Testing Technology of Cosmetics, Zhejiang Institute for Food and Drug Control, Hangzhou, Zhejiang 310004, China. Electronic address: kuangrong@zjyj.org.cn.
  • 6 School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address: junlian_gu@sdu.edu.cn.
PMID: 39069209 DOI: 10.1016/j.jare.2024.07.025
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.

Keywords

Cardiac insulin resistance; Diabetic cardiomyopathy; Oxidative stress; Sulforaphane; p53-TRIB3 axis.

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