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

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.