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

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

doi:10.1016/j.atherosclerosis.2023.117283

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

Atherosclerosis. 2023 Oct:382:117283. doi: 10.1016/j.atherosclerosis.2023.117283. Epub 2023 Sep 14.

Authors

Fernando Garcez Porto¹, Leonardo Yuji Tanaka¹, Tiphany Coralie de Bessa¹, Percillia Victoria Santos Oliveira¹, Júlia Martins Felipe de Souza¹, Daniela Kajihara¹, Carolina Gonçalves Fernandes¹, Patricia Nolasco Santos¹, Francisco Rafael Martins Laurindo²

Affiliations

¹ Laboratorio de Biologia Vascular (LVascBio), LIM-64, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
² Laboratorio de Biologia Vascular (LVascBio), LIM-64, Instituto do Coracao (InCor), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil. Electronic address: francisco.laurindo@hc.fm.usp.br.

PMID: 37774430
DOI: 10.1016/j.atherosclerosis.2023.117283

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 mortality 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, echocardiographic 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 uncovers a novel integrative mechanism coupling redox and biomechanical homeostasis in vascular remodeling.

Keywords: Aortic aneurysm; Aortic dissection; Isoquercetin; Protein disulfide isomerase; Vascular biomechanics.