Heme as a Pro-Inflammatory Stimulus in Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a lethal vascular disease characterized by intramural hemorrhage. This study delineates the signatures of heme and its metabolic imbalance related to progression and inflammation in AAA. Clinical analyses of patients undergoing open AAA surgery show that AAA patients exhibit vascular inflammation, with elevated serum CRP, IL-6, and heme levels correlating with the expression of heme-regulated gene Hmox1/HO-1 (heme oxygenase-1) in the affected aortic wall. Oxidation of hemoglobin to ferri state leading to accumulation of methemoglobin readily releasing heme occurs in human AAA and in angiotensin II (AngII)-induced AAA in apolipoprotein E-deficient mice. Transcriptomic analysis for AngII-induced AAA identifies upregulated genes predominantly enriched in inflammatory signaling, extracellular matrix degradation, oxidative stress pathways, and altered expression of genes related to heme metabolism including Hmox1. Immunohistochemistry for IL1β and TNFα confirms inflammatory activation within AAA tissues. The signatures of heme-responsive gene inductions, enhanced expression of HO-1 and H-ferritin, are detected. Mechanistic studies employing endothelial cells and smooth muscle cells reveal that heme exposure of resident cells markedly enhances the expression of IL1β and ICAM1, as well as the inflammasome component NLRP3, and such inflammatory response is controlled by HO-1. Intervention with Normosang (heme arginate), an HO-1 inducer, attenuates aneurysm progression, whereas HO-1 inhibition by Tin protoporphyrin IX abolishes this protection. Induction of HO-1 accompanied by elevated H-ferritin level also mitigated aortic wall inflammation as reflected by lowering IL1β and TNFα. These findings highlight the heme-HO-1-H-ferritin axis as an element of AAA pathogenesis and a potential therapeutic target.