Investigating abdominal aortic aneurysm mechanisms: searching for new therapeutic targets to restrain inflammation and vascular remodelling
[eng] Abdominal aortic aneurysm (AAA) is a prevalent vascular degenerative disease defined as a focal and permanent dilation of the aorta at the abdominal level. The progressive weakening of the aortic wall can ultimately lead to rupture, a severe consequence associated with high mortality rates. Th...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/220597 |
| Acceso en línea: | https://hdl.handle.net/2445/220597 http://hdl.handle.net/10803/694296 |
| Access Level: | acceso abierto |
| Palabra clave: | Farmacologia cardiovascular Aneurismes aòrtics Biologia molecular Citologia Cardiovascular pharmacology Aortic aneurysms Molecular biology Cytology |
| Sumario: | [eng] Abdominal aortic aneurysm (AAA) is a prevalent vascular degenerative disease defined as a focal and permanent dilation of the aorta at the abdominal level. The progressive weakening of the aortic wall can ultimately lead to rupture, a severe consequence associated with high mortality rates. The key factors contributing to the weakening and bulging of the aortic wall are chronic inflammation, proteolytic degradation of the extracellular matrix, loss of vascular smooth muscle cells (VSMCs) by apoptosis, and increased oxidative stress and neoangiogenesis. Currently, there are no pharmacological treatments to prevent AAA rupture or slow down its progression, and the only therapeutic option is the surgical repair of AAA at high risk of rupture, a procedure associated with high morbi-mortality. Thus, it is imperative to find new therapeutic targets for AAA. In recent years, our group has focused on studying the molecular mechanisms underlying the destructive remodelling of the vascular wall in AAA, postulating new therapeutic targets, with special emphasis on the repositioning of drugs with anti-inflammatory activity already used for other pathologies. In the present study, we found that the Wnt signalling pathway was dysregulated in AAA. In particular, the active form of catenin was increased in the aorta from patients with AAA. In agreement, catenin was also upregulated in the aneurysmal lesions from the classical model of AAA [apolipoprotein E deficient (ApoE-/-) infused with Ang II] compared to control animals. However, the pharmacological inhibition of the Wnt signalling pathway at two levels limited cardiac hypertrophy but had no beneficial effect on preventing AAA. Previous studies from our group observed that the phosphodiesterase 4B (PDE4B) was increased in human AAA by microarray studies. In this study, we confirmed the overexpression of PDE4B in the abdominal aortas from two cohorts of patients. PDE4B was primarily located in inflammatory cells and to a lesser extent in VSMCs. In agreement, a similar profile was detected in the aortas from ApoE-/-mice infused with Ang II. In these mice, PDE4 inhibition with rolipram prevented the formation of Ang II-induced aneurysms by reducing vascular remodelling, MMP activity, inflammation and oxidative stress, without affecting blood pressure or cardiac hypertrophy caused by Ang II. We further analysed the molecular mechanisms underlying the beneficial effects of rolipram. In this context, we demonstrate that rolipram modulates the expression of enzymes involved in redox homeostasis and affects cell signalling pathways implicated in the formation of AAA. Likewise, here we show and induction of the phosphorylated form of ATP-citrate lyase (p-ACLY) in human AAA as well as in two animal models susceptible to Ang II-induced AAA: the ApoE-/- and mice overexpressing the human nuclear receptor NOR-1 (Neuron-derived orphan receptor-1) in the vascular wall (TgNOR-1VSMC). P-ACLY localised to inflammatory infiltrate in the aneurysmal lesions. The preventive treatment with bempedoic acid (BemA), a newly approved drug for the treatment of hypercholesterolemia and dyslipidaemia, protected against AAA formation in Ang II-infused ApoE-/- and TgNOR-1VSMC, without affecting the increase in blood pressure. BemA attenuated the exacerbated vascular remodelling and the disorganisation and rupture of elastic fibres induced by Ang II in these two models. Moreover, ACLY inhibition prevented the recruitment of macrophages and neutrophils within the aneurysmal lesion in experimental AAA. In ApoE-/- mice, the inhibition of ACLY shifted splenic monocytes toward a functionally anti-inflammatory phenotype, and attenuated the systemic inflammation. Overall, these results point to PDE4 as a pharmacological target for AAA and to BemA as a promising therapeutic strategy for AAA. |
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