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
  • 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: [email protected].
  • 5. NMPA Key Laboratory for Animal Alternative Testing Technology of Cosmetics, Zhejiang Institute for Food and Drug Control, Hangzhou, Zhejiang 310004, China. Electronic address: [email protected].
  • 6. School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China. Electronic address: [email protected].
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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