Abstract 4365649: Sortilin inhibition mitigates the severity of calcific aortic valve disease in a minipig model

Abstract

Introduction: Calcific aortic valve disease (CAVD) is a progressive condition that leads to aortic stenosis, heart failure, and premature death. Emerging evidence indicates that oxidative stress plays a significant role in the pathophysiology of CAVD by promoting damage to the endothelium lining the aortic valve. Our previous data provided evidence that sortilin orchestrates a complex intracellular signaling pathway culminating in endothelial dysfunction in mice through increased ROS production. Research Questions: To unveil the potential involvement of sortilin in the molecular mechanisms linking endothelial injury and oxidative stress in the progression of CAVD. Methods: Isolated human valve endothelial cells were used to identify the molecular mechanisms in vitro. Göttingen minipigs were randomly assigned to either a standard diet (SD) or a diet high in fat and cholesterol (HF) for 20 weeks. During this period, they received oral administration of either a placebo or the sortilin inhibitor AF38469. Blood samples were collected at baseline, during, and at the end of treatment for biochemical and oxidative stress marker analyses. Aortic cusps were analyzed histologically for cellularity, collagen, fibrosis, and calcification. Immunohistochemistry and Western blot assessed oxidative stress and osteoblast markers. Vascular reactivity studies evaluated endothelial function in isolated resistance vessels. Results: Immunohistochemistry revealed that the HF diet compromised endothelial integrity on the aortic valve surface, while sortilin inhibition preserved it. Furthermore, the HF diet group exhibited increased oxidative stress, activation of myofibroblast/osteoblast phenotypes, and mineralization in the valve, all of which were reduced by the sortilin inhibitor. Moreover, AF38469 significantly prevented the increased plasma cholesterol ( p< 0.0001) and triglyceride ( p< 0.0001) levels as well as the endothelial dysfunction observed in the placebo-treated HF diet group. Conclusions: Our data suggest that sortilin negatively regulates valvular degeneration by influencing the destruction of endothelial integrity, the increase in inflammation and oxidative stress, thereby highlighting its therapeutic potential in CAVD.