TEK Downregulation Of LOX Propeptide: A Novel Mechanism For Endothelial Cell Protection Following Myocardial Infarction.
TL;DR
A novel interaction between TEK receptor tyrosine kinase (TEK) and signal transducer and activator of transcription 3 (STAT3) is identified, promoting the phosphorylation and nuclear translocation of STAT3 and preventing the upregulation of STAT3 and p-STAT3.
Abstract
Vascular endothelial cells play a crucial role in maintaining the structural integrity and microcirculatory function of the coronary microvasculature. Endothelial dysfunction, a critical pathological process in various cardiovascular diseases including myocardial infarction (MI), leads to reduced myocardial blood flow due to a lack of nitric oxide gas inside blood vessel walls that ultimately causes inflammation, thrombosis and coronary artery obstruction. Therefore, the identification of molecular mechanisms that protect against endothelial cell injury is necessary for effective MI treatment. In this study, we identified a novel interaction between TEK receptor tyrosine kinase (TEK) and signal transducer and activator of transcription 3 (STAT3), promoting the phosphorylation and nuclear translocation of STAT3. In particular, the upregulation of STAT3 and p-STAT3 could be prevented by inhibiting the binding of STAT3 to TEK using specific STAT3 domain inhibitors. Additionally, chromatin immunoprecipitation (ChIP) analysis revealed that STAT3 acts as a transcription factor, binding to the promoter region of lysyl oxidase (LOX) and LOX propeptide (LOX-PP) and inhibiting their transcription. Notably, excessive LOX-PP has been shown to induce endothelial cell injury, leading to reduced nitric oxide synthesis, increased permeability, and impaired functionality in terms of proliferation, migration, and tube formation. These novel findings reveal a new mechanism of endothelial cell injury after myocardial ischemia and may offer new insights for developing future therapeutic approaches.