Lu Guangping, Tang Yufeng, Chen Ou, Guo Yuanfang, Xiao Mengjie, Wang Jie, Liu Qingbo, Li Jiahao, Gao Ting, Zhang Xiaohui, Zhang Jingjing, Cheng Quanli, Kuang Rong, Gu Junlian
School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, China.
J Adv Res. 2025 Jun;72:467-484. doi: 10.1016/j.jare.2024.07.025. Epub 2024 Jul 26.
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.
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.
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.
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 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.
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.
胰岛素抵抗（IR）与多种病理特征相关。尽管在脂肪组织和肝脏中广泛研究了由p53或TRIB3调控的IR，但p53-TRIB3轴在心肌IR中的作用仍不清楚，更重要的是，针对心肌IR的靶向治疗尚不存在。
鉴于萝卜硫素（SFN）对心血管健康有益，探讨SFN是否能预防心肌IR，重点关注p53-TRIB3轴的调节作用，具有特别重要的意义。
使用包括心脏特异性过表达p53的转基因（p53-cTg）小鼠和Trib3基因敲除（Trib3-KO）小鼠的小鼠模型，结合用p53激活剂（nutlin-3a）和抑制剂（pifithrin-α，PFT-α）处理或用p53-shRNA和Trib3-shRNA转染的原代心肌细胞，随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。
在此，我们报告敲低p53可挽救心脏胰岛素刺激的AKT磷酸化，而在糖尿病条件下，nutlin-3a或p53-cTg小鼠上调p53会削弱心肌细胞中的胰岛素敏感性。SFN可显著逆转p53-Tg小鼠中AKT介导的心脏胰岛素信号在糖尿病状态下的减弱，但在p53-cTg小鼠中则无此作用。重要的是，我们发现p53-cTg糖尿病小鼠中TRIB3升高，并证实了p53与TRIB3之间的物理相互作用。Trib3-KO糖尿病小鼠心脏中的胰岛素敏感性有所改善。更具体地说，AMPKα触发的CHOP磷酸化和降解对于p53对Trib3的转录调控至关重要。
总体而言，这些结果表明，SFN抑制p53-TRIB3途径在改善心肌IR中起着意想不到的关键作用，这可能是减轻糖尿病患者糖尿病性心肌病（DCM）的一种有前景的策略。
