Critical Role of Cathepsin L/V in Regulating Endothelial Cell Senescence.

Simple Summary: Endothelial cell senescence has been considered as an initiation in the progress of vascular aging leading to the advancement of cardiovascular diseases, while the mechanism of endothelial cell senescence remains elusive. This study aimed to investigate the critical role of cathepsinL/V in endothelial cell senescence. We found that cathepsinL/V was decreased in senescent endothelial cells, which enhanced aldehyde dehydrogenase 1 family member A2 (ALDH1A2) expression and activated AKT/ERK1/2-P21 pathway, and therefore promoted cellular senescence, which may play an important role in vascular aging. These findings suggest that cathepsinL/V may be a potential therapeutic target in endothelial cell senescence. The senescence of vascular endothelial cells (ECs) is characterized as a hallmark of vascular aging, which leads to the initiation, progress, and advancement of cardiovascular diseases. However, the mechanism of the ECs senescence remains elusive. In this study, thoracic aortas were separated from young (8-week-old) and aged (18-month-old) mice. Decreased Ctsl expression and increased vascular remodeling were observed in senescent aorta. H2O2 was used to induce human umbilical vein endothelial cells (HUVECs) senescence, as shown by increased SA-β-gal positive cells and upregulated p21 level. CTSV significantly decreased after H2O2 treatment, while over-expression of CTSV by adenovirus reduced cellular senescence. RNA sequencing analysis was conducted subsequently, and ALDH1A2 was observed to significantly increased in H2O2 group and decreased after over-expression of CTSV. This result was further confirmed by RT-PCR and WB. Moreover, over-expression of CTSV reduced the increase of ERK1/2 and AKT phosphorylation induced by H2O2. Additionally, retinoic acid (RA), the major production of ALDH1A2, was added to CTSV over-expressed senescent HUVECs. Administration of RA activated AKT and ERK1/2, induced the expression of p21, and enhanced SA-β-gal positive cells, while not affecting the expression of CTSV and ALDH1A2. These results were further confirmed in doxorubicin (DOX)-induced senescent ECs. In conclude, we have identified that Ctsl/CTSV plays a key role in ECs senescence by regulating ALDH1A2 to activate AKT/ ERK1/2-P21 pathway. Therefore, targeting Ctsl/CTSV may be a potential therapeutic strategy in EC senescence. [ABSTRACT FROM AUTHOR]