l‐Homocysteine‐induced cathepsin V mediates the vascular endothelial inflammation in hyperhomocysteinaemia

BACKGROUND AND PURPOSE Vascular inflammation, including the expression of inflammatory cytokines in endothelial cells, plays a critical role in hyperhomocysteinemia-associated vascular diseases. Cathepsin V, specifically expressed in humans, is involved in vascular diseases through its elastolytic and collagenolytic activities. The aim of this study was to determine the effects of cathepsin V on the L-homocysteine (L-Hcy)-induced vascular inflammation. EXPERIMENTAL APPROACH A high methionine diet-induced hyperhomocysteinemic mice model was used to assess the cathepsin V expression and vascular inflammation. Cultures of HUVECs were challenged with L-Hcy and cathepsin L/V inhibitor SID to assess the pro-inflammatory effects of cathepsin V. Transfection and anti-sense techniques were utilized to investigate the influences of cathepsin V on the dual specificity protein phosphotases (DUSPs) and mitogen-activated protein kinase (MAPK) pathways. KEY RESULTS We revealed that cathepsin L (human cathepsin V homologous) was increased in the thoracic aorta endothelial cells of hyperhomocysteinemic mice, L-Hcy promoted cathepsin V expression in HUVECs. SID suppressed the activity of cathepsin V, reversed up-regulation of inflammatory cytokine (IL-6, IL-8, TNFα), adhesion and chemotaxis of leukocyte, and vascular inflammation induced by L-Hcy in vivo and in vitro. Increased cathepsin V promotes the degradation of DUSP6 and DUSP7, phosphorylation and subsequent nuclear translocation of ERK1/2, phosphorylation of STAT1 and expression of IL-6, IL-8, TNFα. CONCLUSION AND IMPLICATIONS This study has therefore delineated a novel mechanism that L-Hcy-induced cathepsin V mediated vascular endothelial inflammation under high homocysteine condition partly via ERK1/2/STAT1 pathway. This mechanism could represent a potential therapeutic target in hyperhomocysteinemia-associated vascular diseases.