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

# metadata.dc.contributor.other[].value
Universitat de Barcelona. Departament de Biomedicina

# metadata.dc.description.abstract[].value
[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.

# metadata.dc.source[].value
Tesis Doctorals - Departament - Biomedicina

# metadata.dc.title[].value
Insights in the pathogenesis of the aortic aneurysm in Marfan syndrome and new therapeutic approaches