Abstract

ATP-binding cassette B8 (ABCB8) is a mitochondrial iron exporter known to prevent iron-dependent oxidative stress in cardiomyocytes and endothelial cells. However, the role of ABCB8 in endothelial and vascular function remains unclear. Here, we identified ABCB8 as a key regulator of vascular homeostasis. We found that loss of ABCB8 in endothelial cells triggers a pro-inflammatory transcriptional program, marked by upregulation of TGF-β isoforms and activation of TGF-β signalling. We show that TGF-β functions as an iron effector that drives mitochondrial reactive oxygen species (ROS) and mitochondrial damage, revealing a new ABCB8–iron–TGF-β axis in endothelial cells. In endothelial-specific inducible Abcb8 knockout mice (Abcb8ECKO), ABCB8 deficiency leads to endothelial activation, pro-inflammatory transcriptional reprogramming of smooth muscle cells (SMCs), fibroblasts and immune cells. Combination of intravital imaging experiments with ex vivo treatment of aortae from Abcb8ECKO with the iron chelator deferoxamine or TGF-β receptor I inhibitor SB431542 suggests that ABCB8 suppresses iron-dependent TGF-β-mediated vascular inflammation in the aorta. In agreement, endothelial ABCB8 deficiency exacerbates atherosclerosis and hypertension in Apoe−/− knockout mice, uncovering a critical atheroprotective role for ABCB8 and supporting its therapeutic potential in vascular disease.