Evidence for a protective role of Protein Disulfide Isomerase-A1 against aortic dissection

Autor(es)

Porto, Fernando Garcez ; Tanaka, Leonardo Yuji ; de Bessa, Tiphany Coralie ; Oliveira, Percillia Victoria Santos ; de Souza, Julia Martins Felipe ; Kajihara, Daniela ; Fernandes, Carolina Goncalves ; Santos, Patricia Nolasco ; Laurindo, Francisco Rafael Martins

• Tipo de documento: Artigo Científico
• Fonte: ATHEROSCLEROSIS; v. 382, p. 9-pg., 2023-09-27.

Resumo

Background and aims: Redox signaling is involved in the pathophysiology of aortic aneurysm/dissection. Protein Disulfide Isomerases and its prototype PDIA1 are thiol redox chaperones mainly from endoplasmic reticulum (ER), while PDIA1 cell surface pool redox-regulates thrombosis, cytoskeleton remodeling and integrin activation, which are mechanisms involved in aortic disease. Here we investigate the roles of PDIA1 in aortic dissection. Methods: Initially, we assessed the outcome of aortic aneurysm/dissection in transgenic PDIA1-overexpressing FVB mice using a model of 28-day exposure to lysyl oxidase inhibitor BAPN plus angiotensin-II infusion. In a second protocol, we assessed the effects of PDIA1 inhibitor isoquercetin (IQ) against aortic dissection in C57BL/6 mice exposed to BAPN for 28 days. Results: Transgenic PDIA1 overexpression associated with ca. 50% (p = 0.022) decrease (vs.wild-type) in mor-tality due to abdominal aortic rupture and protected against elastic fiber breaks in thoracic aorta. Conversely, exposure of mice to IQ increased thoracic aorta dissection-related mortality rates, from ca. 18%-50% within 28-days (p = 0.019); elastic fiber disruption and collagen deposition were also enhanced. The structurally-related compound diosmetin, which does not inhibit PDI, had negligible effects. In parallel, stretch-tension curves indicated that IQ amplified a ductile-type of biomechanical failure vs. control or BAPN-exposed mice aortas. IQ-induced effects seemed unassociated with nonspecific antioxidant effects or ER stress. In both models, echo-cardiographic analysis of surviving mice suggested that aortic rupture was dissociated from progressive dilatation. Conclusions: Our data indicate a protective role of PDIA1 against aortic dissection/rupture and potentially un-covers a novel integrative mechanism coupling redox and biomechanical homeostasis in vascular remodeling. (AU)

• Processo FAPESP: 21/14131-6 - Modulação da resposta vascular a lesão pela proteína dissulfeto isomerase-A1
• Beneficiário: Júlia Martins Felipe de Souza
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 13/07937-8 - Redoxoma
• Beneficiário: Ohara Augusto
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 18/07230-5 - Mecanismos subcelulares envolvidos na convergência entre homeostase mecânica e redox na regulação vascular
• Beneficiário: Leonardo Yuji Tanaka
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 14/24511-7 - Mecanismos e implicações da sinalização via mTORC1 no fenótipo cardiovascular da Síndrome de Marfan
• Beneficiário: Patricia Nolasco Santos
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 19/03617-5 - Proteína Dissulfeto Isomerase-A1 (PDIA1) citosólica: um novo mecanismo tiol-redox de sinalização celular
• Beneficiário: Percíllia Victória Santos de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 18/07511-4 - Contatos retículo endoplasmático-membrana plasmática como possíveis sítios de interação da sinalização redox dependente de NADPH oxidase NOx
• Beneficiário: Tiphany Coralie de Bessa
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 17/11410-6 - Dissulfeto isomerase de proteínas (PDI)-A1 peri/epicelular: um novo alvo terapêutico no Aneurisma de Aorta
• Beneficiário: Fernando Garcez Porto
• Modalidade de apoio: Bolsas no Brasil - Doutorado