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

Abstract

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 proinflammatory 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 with 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, whereas the mRNA expression remained unaffected. Suppressing iNOS in macrophages alleviated SMCs apoptosis by decreasing nitric oxide generation in a coculture 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.NEW & NOTEWORTHY This article illustrates the role of macrophage-derived heme oxygenase-1 (HO-1) in the development of abdominal aortic aneurysm (AAA). HO-1 deletion in macrophages hindered AAA development by reducing inducible nitric oxide synthase (iNOS)-dependent peroxynitrite production and smooth muscle cells (SMCs) apoptosis in vivo. Mechanistically, inhibition of HO-1 reduced the stimulated iNOS protein production in macrophages by lipopolysaccharide/interferon-γ. Moreover, suppressing iNOS in macrophages prevented SMCs apoptosis by decreasing nitric oxide generation in vitro.

Keywords: abdominal aortic aneurysm; heme oxygenase-1; inducible nitric oxide synthase; macrophage; peroxynitrite.