Macrophage heme oxygenase-1 modulates peroxynitrite-mediated vascular injury and exacerbates abdominal aortic aneurysm development

Inflammatory reactions mediated by macrophages are profoundly related to the depletion of smooth muscle cells (SMCs) in abdominal aortic aneurysm (AAA) development. The findings from our previous investigation indicate that heme oxygenase-1 (HO-1) in macrophages exacerbates pro-inflammatory responses and oxidative damage. Therefore, the aim of this work was to gain insight into the function of HO-1 derived from macrophages and elucidate the underlying molecular mechanisms involved in AAA development. In this study, we discovered a dramatic increase in HO-1 expression in the infiltrated macrophages in experimental calcium phosphate-induced AAA tissues. Myeloid conditional HO-1-deficient mice displayed slower luminal area enlargement, as well as diminished inducible nitric oxide synthase (iNOS)-positive M1 macrophage activation, peroxynitrite generation and SMCs apoptosis in aneurysmal tissues compared to littermate controls. Furthermore, we showed that inhibiting HO-1 eliminated the protein expression of iNOS induced by lipopolysaccharide/interferon-γ in bone marrow-derived macrophages, while the mRNA expression remained unaffected. Suppressing iNOS in macrophages alleviated SMCs apoptosis by decreasing NO generation in a co-culture system in vitro. In summary, our study illustrates that macrophage-derived HO-1 strengthens AAA development through boosting the production of iNOS-dependent peroxynitrite and the deterioration of SMCs. These findings reveal potential therapeutic targets for resolving aneurysmal diseases.