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

Author(s)

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

• Document type: Journal article
• Source: ATHEROSCLEROSIS; v. 382, p. 9-pg., 2023-09-27.

Abstract

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)

• FAPESP's process: 21/14131-6 - Modulation of vascular injury response by protein disulfide isomerase-A1
• Grantee: Júlia Martins Felipe de Souza
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 18/07230-5 - Subcellular mechanisms underlying the convergence between redox and mechanic homeostasis on vascular regulation
• Grantee: Leonardo Yuji Tanaka
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 14/24511-7 - Mechanisms and implications of the mTORC1 signaling pathway in the cardiovascular phenotype of Marfan Syndrome
• Grantee: Patricia Nolasco Santos
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 19/03617-5 - Cytosolic Protein Disulfide Isomerase-A1 (PDIA1): a novel thiol-redox mechanism in cell signaling
• Grantee: Percíllia Victória Santos de Oliveira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/07511-4 - Endoplasmic reticulum-plasma membrane contacts as hubs for NOx NADPH oxidase-dependent cellular redox signaling
• Grantee: Tiphany Coralie de Bessa
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/11410-6 - Protein Disulfide Isomerase (PDI)-A1 peri/epicellular: a new therapeutic target in Aortic Aneurysm
• Grantee: Fernando Garcez Porto
• Support Opportunities: Scholarships in Brazil - Doctorate