Insights in the pathogenesis of the aortic aneurysm in Marfan syndrome and new therapeutic approaches

Abstract

[eng] The objective of this thesis was to investigate the effect of a potent inhibitor peptide (P144) targeting transforming growth factor β (TGFβ) on the development of aortic aneurysms in a mouse model of Marfan syndrome. We also aimed to assess the role of oxidative stress and hyperuricemia in the progression of aortic aneurysms in Marfan syndrome. To investigate the effect of P144, a chimeric gene encoding the P144 peptide linked to apolipoprotein A-I was delivered using a hepatotropic adeno-associated vector. Two experimental approaches were employed: a preventive treatment administered before the onset of aortic aneurysms and a palliative treatment administered once the aneurysm was already formed. The preventive treatment with P144 successfully prevented the onset of aortic dilation and improved the morphology of elastic fibers and normalized TGFβ signaling. However, the palliative treatment did not halt the progression of the aneurysm. Furthermore, we examined the role of oxidative stress and hyperuricemia in aortic aneurysm development. We found increased production of reactive oxygen species (ROS) and upregulation of XOR, an enzyme involved in ROS production, in both human Marfan syndrome patients and mouse models. Treatment with the XOR inhibitor allopurinol effectively halted the progression of aortic aneurysms in Marfan syndrome mice and mitigated associated endothelial dysfunction and collagen remodeling. Additionally, we investigated the association between hyperuricemia and aortopathy in Marfan syndrome mice and found that hyperuricemia did not exacerbate or alleviate aortic aneurysm development. The findings of this study suggest that P144 is effective in preventing the onset of aortic aneurysms by reducing excessive TGFβ signaling. Oxidative stress plays a role in the formation and progression of aortic aneurysms in Marfan syndrome, and treatment with allopurinol as an antioxidant can interfere with the progression of aortic aneurysms. However, hyperuricemia does not interfere with the development of aortic aneurysms or cardiopathy in Marfan syndrome mice. These results highlight the importance of targeting TGFβ signaling and oxidative stress during the early stages of aortic disease progression in individuals with Marfan syndrome.