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| Author(s): |
Fernando Garcez Porto
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) |
| Defense date: | 2022-11-08 |
| Examining board members: |
Francisco Rafael Martins Laurindo;
Antonio Augusto Barbosa Lopes;
Marcelo Larami Santoro
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| Advisor: | Francisco Rafael Martins Laurindo |
| Abstract | |
Redox signaling is involved in the pathophysiology of aortic aneurysm/dissection. Protein Disulfide Isomerases and their prototype PDIA1 are thiol redox proteins present mainly in the endoplasmic reticulum. Its cell surface and extracellular pool redox-dependently regulates processes such as thrombosis, cytoskeletal remodeling and integrin activation, which are mechanisms involved in aortic disease. Here we investigate the role of PDIA1 in aortic dissection. We initially evaluated the outcome in an aortic aneurysm/dissection model in transgenic mice overexpressing PDIA1 using a 28-day exposure model to the BAPN lysyl oxidase inhibitor in drinking water associated with an angiotensin-II infusion by implantable osmotic pump. In a second protocol, we evaluated the effects of PDIA1 inhibitor isoquercetin (IQ) on aortic dissection in mice exposed to BAPN for 28 days. Overexpression of PDIA1 in transgenic FVB background mice was associated with about 50% (p=0.022) reduction in mortality rates from abdominal aortic rupture and protection against elastic fiber breaks in the thoracic aorta. On the other hand, exposure to the PDIA1 inhibitor, IQ in C57BL/6 mice markedly increased mortality rates related to thoracic aortic dissection, from about 18% to 50% at 28 days (p = 0.019). The breakdown of elastic fibers and collagen deposition were also shown to be increased in the aortas of these mice. In parallel, a viscoelasticity assay, evaluating vascular tension in response to progressive stretching, indicated that IQ promoted a ductile-type of biomechanical failure when compared to control aortas or aortas from mice exposed to BAPN, which demonstrated a sudden pattern of failure. IQ-induced effects appear not to be associated with nonspecific antioxidant effects or endoplasmic reticulum stress. In both models, echocardiographic analysis evaluating surviving mice suggested that aortic rupture was dissociated from progressive dilatation. In summary, our data indicate a protective role of PDIA1 against aortic dissection/rupture and potentially reveal a new integrative mechanism that couples redox homeostasis and biomechanics in vascular remodeling (AU) | |
| 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 |