A Dual Role of Heme Oxygenase-1 in Angiotensin II-Induced Abdominal Aortic Aneurysm in the Normolipidemic Mice

Abstract

Abdominal aortic aneurysm (AAA) bears a high risk of rupture and sudden death of the patient. The pathogenic mechanisms of AAA remain elusive, and surgical intervention represents the only treatment option. Heme oxygenase-1 (HO-1), a heme degrading enzyme, is induced in AAA, both in mice and humans. HO-1 was reported to mitigate AAA development in an angiotensin II (AngII)-induced model of AAA in hyperlipidemic ApoE-/- mice. Since the role of hyperlipidaemia in the pathogenesis of AAA remains controversial, we aimed to evaluate the significance of HO-1 in the development and progression of AAA in normolipidemic animals. The experiments were performed in HO-1-deficient mice and their wild-type counterparts. We demonstrated in non-hypercholesterolemic mice that the high-dose of AngII leads to the efficient formation of AAA, which is attenuated by HO-1 deficiency. Yet, if formed, they are significantly more prone to rupture upon HO-1 shortage. Differential susceptibility to AAA formation does not rely on enhanced inflammatory response or oxidative stress. AAA-resistant mice are characterized by an increase in regulators of aortic remodeling and angiotensin receptor-2 expression, significant medial thickening, and delayed blood pressure elevation in response to AngII. To conclude, we unveil a dual role of HO-1 deficiency in AAA in normolipidemic mice, where it protects against AAA development, but exacerbates the state of formed AAA.

Pharmacological Inhibition of MMP-12 Exerts Protective Effects on Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice

“…Furthermore, HMOX1 can downregulate MMP-12 expression [ 54 ], and although not directly attributable to MMP-12, HMOX1 deficiency aggravated AAA development in Ang II-infused Apoe −/− mice [ 55 ]. However, HMOX1 deficiency appears protective in normocholesterolemic mice, limiting AAA formation [ 56 ], similar to the proposed dual actions of MMP-12 [ 29 ].…”

A highly selective mPGES-1 inhibitor to block abdominal aortic aneurysm progression in the angiotensin mouse model

“…Increased age is a significant risk factor for the development of AAA in humans 38 . Similarly, the incidence of AAA following AngII infusion has been shown to be increased in aged (18–20 months) nonhyperlipidemic C57 wild-type mice, as compared to younger mice (2–3 months).…”

Reactive Oxygen Species and Oxidative Stress in Vascular-Related Diseases

“…HO-1 has been reported to attenuate the development of AA in mouse models induced by Ang-II. However, Kopacz et al revealed the dual role of HO-1 in AA formation, which can prevent the development of AA while simultaneously exacerbating the formation of AA states and reducing the risk of rupture [ 100 , 101 ].…”