The mechanism of sterile inflammatory response drive the development of vessle remodeling and intimal hyperplasia (IH) was not fully understood. We hypothesis that myeloid differentiation protein-88 (MyD88) in macrophages, the major endocellular adaptor molecule that mediate most toll like receptors (TLRs) induced inflammation, activates processes leading to vessle remodeling via upregulation of cathepsin L activity.Design and Method:
Carotid artery wire injury was applied in C57BL/6 wild type (WT) mice, MyD88loxP/loxP mice, Lyz-MyD88−/− mice and cathepsin L−/− mice to investigate vessel remodeling and intimal formation. H&E and Immunofluorescent staining were used to determine the intimal to medial area (I/M) and expression of CD68+cell. Reverse Transcription-Quantitative PCR was used to measure gene expression in carotid arteries subjected to acute wire injury. Fluorometric Cathepsin L Activity Assay was applied to examine cathepsin L enzymatic activity in carotid arteries.Results:
We demonstrated the deletion of MyD88 on macrophages prevents vessle remodeling and IH, monocyte recruitment and cathepsin L activation following carotid artery injury. An increase in cathepsin L activity was observed in the injured arteries throughout 28 days and peaked at 7days. We showed the deletion of cathepsin L significantly inhibits IH. A HIV protease inhibitor saquinavir (SQV), showed specifically block recombined mouse cathepsin L activity in vitro, predominately inhibits IH, upregulation of cathepsin L activity, MyD88 and IL6 mRNA expression after endoluminal arterial injury.Conclusions:
These findings demonstrated that MyD88- Cathepisn L signaling as a critical pathway that drives IH. The evidence also provide SQV could be a potential therapeutic reagent attenuate IH targeting on suppressing cathespin L enzymatic activity and MyD88 upregulation following the endoluminal arterial injury.