Oxidation of low-density lipoprotein by hemoglobin causes pulmonary microvascular endothelial barrier dysfunction through lectin-like oxidized LDL receptor 1

Abstract

Elevated circulating cell-free hemoglobin (Hb) is a pathological driver of endothelial injury and contributes to disease severity and organ dysfunction during several pathologies, including sickle cell disease, pulmonary hypertension, primary graft dysfunction after lung transplantation, and sepsis. However, the signaling mechanisms involved in Hb-mediated pulmonary microvascular endothelial barrier dysfunction are not well understood. One mechanism by which Hb may contribute to microvascular endothelial barrier dysfunction is through its ability to oxidize circulating lipids and lipoproteins, including low-density lipoproteins (LDLs). In this study, we hypothesized that oxidation of LDL (oxLDL) by Hb (Hb-oxLDL) disrupts the pulmonary microvascular endothelial barrier via the scavenger receptor for oxLDL, lectin-like oxidized LDL receptor 1 (LOX-1). We stimulated primary human pulmonary microvascular endothelial cells with Hb-oxLDL and found significant disruption to the endothelial barrier. Barrier dysfunction by Hb-oxLDL was partially prevented by haptoglobin or LOX-1 inhibitor. We also found that oxidation of LDL by heme was sufficient to disrupt the endothelial barrier. Together, these data demonstrate that oxidation of LDL by Hb disrupts the pulmonary microvascular endothelial barrier through the LOX-1 receptor, indicating a potential mechanism for Hb-mediated microvascular injury during inflammatory and hemolytic conditions.NEW & NOTEWORTHY This study demonstrates that oxidation of low-density lipoproteins (LDLs) by hemoglobin or heme disrupts the pulmonary microvascular endothelial barrier; the scavenger receptor lectin-like oxidized LDL receptor 1 mediates this response. This study reveals a novel mechanism by which the pulmonary microvascular endothelium could be targeted for therapeutic intervention during hemolytic or inflammatory pathologies.

Keywords: LOX-1; barrier dysfunction; endothelial; hemoglobin; lipoprotein.