Abstract 13203: CD36 Regulates Factor VIII Secretion From Liver Endothelial Cells

Abstract

Introduction: Abnormal levels of the coagulation factor VIII (FVIII) are a risk factor for venous thromboembolism (VTE). Genome-wide association studies have identified novel candidate gene associations that may regulate FVIII levels in humans, including CD36. Hypothesis: We hypothesized that CD36 regulates FVIII release from endothelial cells. Methods and Results: We identified a subset of human liver endothelial cells (HLEC) expressing FVIII and purified them using a differentially expressed cell surface protein CD32. CD32+ HLEC expressed FVIII, transported FVIII in intracellular vesicles, and secreted FVIII. We stimulated CD36 signaling or silenced CD36 to test the effect of CD36 on FVIII release. Oxidized LDL (oxLDL), a CD36 agonist, increased endothelial release of FVIII. Conversely, silencing CD36 decreased FVIII release. We searched for an intracellular signaling pathway that mediates CD36 stimulation of FVIII secretion and found that oxLDL increased p38 activity and a p38 inhibitor decreased FVIII release. Conclusions: Taken together, our data show that CD36 stimulates FVIII release through a p38 dependent pathway in specialized liver endothelial cells. These results validate genetic epidemiology data linking CD36 to FVIII levels in humans and provide new insights into the regulation of FVIII levels.