TXNIP Is Positioned as a Key Mediator of Hyperglycemia-Induced Vascular Senescence

Thioredoxin-interacting protein (TXNIP) is regarded as a potential therapeutic target in type 2 diabetes. Hyperglycemia can upregulate the expression of TXNIP in various cell types, thereby inducing oxidative stress. However, the regulatory mechanisms by which this protein modulates vascular function in the aorta remain incompletely elucidated. This study aimed to investigate the response of TXNIP to high glucose in vascular smooth muscle cells (VSMCs) and elucidate the underlying molecular mechanisms. We demonstrated that the carbohydrate-responsive element-binding protein (ChREBP) acts as an upstream transcriptional activator of TXNIP and TXNIP induces cellular senescence by suppressing AKT phosphorylation. Concurrently, senescence leads to activation of p53 and increased expression of the ERBB receptor feedback inhibitor 1 (also known as Mig6), with the upregulated Mig6 in turn resulting in negative feedback inhibition of the activity of the epidermal growth factor receptor, thereby further promoting the development of atherosclerosis. Our findings identify the ChREBP/TXNIP/AKT axis as a novel pathway driving VSMC senescence in a hyperglycemic environment and establish its critical role in promoting atherosclerotic progression. This highlights its potential as a therapeutic target in diabetic macrovascular complications.

This study identifies the carbohydrate-responsive element-binding protein as the direct transcriptional activator of TXNIP in vascular smooth muscle cells under conditions of hyperglycemia. Aorta-specific TXNIP knockdown demonstrates therapeutic potential by alleviating arterial stiffness and attenuating atherosclerotic plaque in diabetic mice. Pharmacologic inhibition of TXNIP or activation of AKT ameliorates the senescent phenotype, highlighting a druggable pathway in diabetic vasculopathy.