Heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression

Abstract

Hemorrhage and hemolysis with subsequent heme release are implicated in many pathologies. Endothelial cells (ECs) encounter large amount of free heme after hemolysis and are at risk of damage from exogenous heme. Here we show that hemorrhage aggravates endoplasmic reticulum (ER) stress in human carotid artery plaques compared to healthy controls or atheromas without hemorrhage as demonstrated by RNA sequencing and immunohistochemistry. In EC cultures, heme also induces ER stress. In contrast, if cultured ECs are pulsed with heme arginate, cells become resistant to heme-induced ER (HIER) stress that is associated with heme oxygenase-1 (HO-1) and ferritin induction. Knocking down HO-1, HO-2, biliverdin reductase, and ferritin show that HO-1 is the ultimate cytoprotectant in acute HIER stress. Carbon monoxide-releasing molecules (CORMs) but not bilirubin protects cultured ECs from HIER stress via HO-1 induction, at least in part. Knocking down HO-1 aggravates heme-induced cell death that cannot be counterbalanced with any known cell death inhibitors. We conclude that endothelium and perhaps other cell types can be protected from HIER stress by induction of HO-1, and heme-induced cell death occurs via HIER stress that is potentially involved in the pathogenesis of diverse pathologies with hemolysis and hemorrhage including atherosclerosis.

Preterm Intraventricular Hemorrhage-Induced Inflammatory Response in Human Choroid Plexus Epithelial Cells

“…In addition, the presence of heme is a well-established danger-associated molecular pattern, which binds to TLR4 to induce immune responses [28]. In ECs, ferryl hemoglobin induces intercellular gap formation and decreases junctional resistance with enhanced monocyte adhesion [27], while heme can result in endoplasmic reticulum stress that is potentially involved in the hemolysis and hemorrhage-associated pathologies [29]. In the present study, we addressed the pro-oxidant and pro-inflammatory effects of the CSF with different IVH origins on choroid plexus epithelial cells.…”

Overview on hydrogen sulfide-mediated suppression of vascular calcification and hemoglobin/heme-mediated vascular damage in atherosclerosis

“…ER stress plays a significant role in atherosclerosis [ 151 , 159 ]. Considering that H 2 S protects against ER stress in many conditions [ 160 ], it is reasonable to hypothesize that H 2 S might protect against pathologic ER stress associated with VC.…”