Dr. Kai-Chien Yang’s Team discovered the novel atherorelevant mechano-transduction mechanisms, findings published in Science Advances
An international collaborative study led by Dr. Kai-Chien Yang, Associate Professor of NTU’s Department and Graduate Institute of Pharmacology, discovered the novel atherorelevant mechano-transduction mechanisms mediated by thioredoxin domain containing 5 (TXNDC5) in vascular endothelial cells and demonstrated the therapeutic potential of targeting endothelial TXNDC5 against atherosclerosis. This finding was recently published in Science Advances.
Atherosclerosis is the leading cause of morbidity and mortality worldwide. Although atherosclerotic lesions typically occur in arterial curvatures and bifurcations, where disturbed flow (DF) activates endothelial cells via mechano-transduction mechanisms, current therapies for atherosclerosis mainly target systematic risk factors (e.g. hypercholesterolemia and hypertension) but not the vasculature per se. This underscores the significance to identify novel atherosclerosis-causing mechanosensitive mechanisms and moreover, develop novel vascular wall-targeted therapeutic approaches.
TXNDC5, an endothelium-enriched endoplasmic reticulum (ER) protein, is responsible for extracellular matrix (ECM) protein folding and linked to cellular redox balance. Dr. Yang and his team have identified TXNDC5 as a critical mediator of organ fibrosis, including the heart (Shih et al, Circulation Research 2018), lungs (Lee et al, Nature Communications 2020), kidneys (Chen et al, Journal of Clinical Investigation 2021), and liver (Hung et al, Gut 2021) fibrosis. Of note, TXNDC5 is also highly expressed in endothelial cells. Dr. Chih-Fan Yeh, a cardiologist at NTU Hospital and also a Ph.D. student at Yang lab, later demonstrated in his research that DF activates endothelial TXNDC5 to destabilize eNOS (endothelial nitric oxide synthase) protein and promote atherosclerosis in mice.
Dr. Yang’s team identified that TXNDC5 expression was increased in human and mouse atherosclerotic lesions and induced in endothelium subjected to DF. Exploiting complementary in vitro and in vivo experiments using newly generated mouse models, the team found that endothelium-specific Txndc5 deletion could alleviate DF-induced atherosclerosis. Moreover, nanoparticles formulated to deliver Txndc5-targeting CRISPR-Cas9 plasmids driven by an endothelium-specific promoter (CDH5) significantly increase eNOS protein and reduce atherosclerosis in hyperlipidemic mice, showing the potential of targeting endothelial TXNDC5 to treat atherosclerosis.
Recently, the COVID-19 vaccine and lipid lowering agents have demonstrated the safety and efficacy of genome editing therapy. Inspired by this technology, Dr. Yang and his team will continue working on developing novel therapeutic strategies targeting TXNDC5, hoping to offer a more effective approach to mitigate atherosclerosis and improve patients' outcomes.
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