Abdominal aortic aneurysm (AAA) with potentially fatal outcomes affects cardiovascular
health via inflammation-related abnormalities. We revealed the presence of the oxidized
hemoglobin (Hb), ferrylHb in the circulation in patients diagnosed with ruptured AAA.
The aim of our study was to identify the source of oxidation of Hb in human hemorrhaged
AAA and in an angiotensin II provoked AAA model in mice leading to generation of ferrylHb
and to describe its fate in the pathophysiology. We demonstrate that two electron
oxidations of Hb leading to the formation of ferrylHb with the characteristics of
oxidation of βCys93, αCys104, and βCys112 residues is the terminal product of the
interaction of neutrophils and macrophages with Hb in the hemorrhaged AAA. This oxidized
Hb, ferrylHb is taken up by neutrophils and macrophages via CD163 mediated endocytosis
with subsequent activations including peptidylarginine deiminase 4 (PAD4) driven NETosis,
liberation of elastase, myeloperoxidase and subsequent degradation of extracellular
matrix. AAA exhibits increased expression of CD163 in macrophages and neutrophils
revealed to be inducible by ferrylHb involving PAD4 signaling. RNA-seq analysis demonstrated
that human ruptured AAA has a unique transcriptomic profile, different from healthy
aorta, with a 43 % overlap in the differential gene expressions of human macrophages
exposed to ferrylHb. Among these 884 genes, we found inflammatory-, angiogenesis-,
and tissue remodeling gene clusters. These data suggest that oxidation of Hb to ferryl
state and the interactions of neutrophils and macrophages with ferrylHb within aortic
wall contribute to AAA progression.
