Mingyi Chen
UT Southwestern Medical Center, USA
Title: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a therapeutic target of sickle cell disease vasculopathy
Biography
Biography: Mingyi Chen
Abstract
Sickle cell disease (SCD) is a recessively inherited disorder that affects hemoglobin structure, function and stability. Although the principal manifestation of SCD is anemia, the significant morbidity and mortality of SCD is due to vaso-occlusive complications. Strokes in children and adults with SCD continue to be a major cause of morbidity and mortality, ∼50% of the children with SCD will have either an overt or silent cerebral infarct before their 18th birthday. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has been identified as a major receptor for oxidized low-density lipoprotein (ox-LDL) as well as phosphatidylserine of aged RBC cells in endothelial cells. We have recently reported increased expression of LOX-1 in human vascular endothelial cells exposed to sickle erythrocytes, as well as in the vessels of SCD patients with vaso-occlusive damage, suggesting a possible causative link between the increased expression of LOX-1 and SCD vasculopathy. The sickle erythrocyte/LOX-1 axis plays a key role in initiating the vicious cycle of SCD that results in vaso-occlusion. The mechanism involves LOX-1 serving as a tether that attaches sickle red blood cells to vascular endothelial cells. This in turn causes signaling amplification that involves upregulation of LOX-1 expression, oxidative stress, and the release of thromboxane A2 that results in further platelet activation/aggregation and vasoconstriction, ultimately leading to vaso-occlusive events and the clinical manifestations of SCD. We anticipate the findings could also lead to the identification of useful therapeutic strategies for the effective clinical management of this debilitating inherited disease.