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| Author(s): |
Aline Garcia Fedoce
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2022-12-13 |
| Examining board members: |
Rita de Cassia Aleixo Tostes Passaglia;
Luiz Guilherme de Siqueira Branco;
Ricardo Machado Xavier
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| Advisor: | Rita de Cassia Aleixo Tostes Passaglia |
| Abstract | |
Cardiovascular diseases (CVD) are the major cause of mortality in rheumatoid arthritis (RA). Chronic inflammation results in perivascular adipose tissue (PVAT) dysfunction, i.e. loss of its anticontractile effect, leading to CVD. The adipokine resistin, via receptors for adenylate cyclaseassociated protein 1 (CAP1) on monocytes/macrophages, promotes adipose tissue inflammation with increased chemocytokines release and macrophage recruitment, events associated with PVAT dysfunction. In addition, circulating and synovial concentrations of resistin are increased in RA. Therefore, in this study, we tested the hypothesis that resistin via CAP1 contributes to PVAT and vascular dysfunction by increasing macrophage recruitment and inflammatory mediators, in an experimental model of antigen-induced arthritis (AIA). Murine resistin knockout mice (RTN- / - ) and mice that do not express murine resistin but express human resistin on monocytes/macrophages (hRTN+/ - / - ) and their respective controls [Wild type: (WT) C57bl/6], male and female, underwent a chronic AIA model with 2 immunizations followed by 5 intra-articular injections. AIA assessment parameters, including the frequency of CD4+ T cells and interleukin-17 (IL-17) in lymph nodes, joint diameter, pain hypernociception, and the histopathological score, did not differ between the RTN- / - , hRTN+ / - / - ), and WT groups. PVAT still kept its anti-contractile effect, determined in response to contractions to phenylephrine (PE) and acetylcholine (ACh). However, in WT AIA, males and females, the PVAT completely lost its anti-contractile effect, independently of the endothelium, and no longer kept the vasodilatory response to ACh, which was independent on the PVAT. The potency of sodium nitroprusside (NPS) was decreased in arteries with PVAT from WT AIA mice. Resistin expression increased in the PVAT, and serum of WT AIA animals. Incubation of arteries with murine or human resistin lead to PVAT dysfunction in WT and hRTN+/ - / - animals, similar to the observed in AIA. Furthermore, RTN- / - AIA animals were protected from PVAT dysfunction, while hRTN+/ - / - AIA animals lost the PVAT anti-contractile effect similar to WT AIA. There were no differences in the morphological aspects of arteries and adipocytes between the AIA groups. Gene expression of M1 and M2 macrophages\' markers was greater in hRTN+/ - / - AIA animals compared to WT AIA and RTN- / - AIA mice. Protein concentration of the inflammatory markers TNF-α, IL-1β, IL-17, IL-6, and IL-10 were higher in the hRTN+ / - / - AIA group compared to the WT AIA, RTN- / - AIA, and control. However, resisitin deletion, RTN- / - AIA mice, prevented the increase of these inflammatory markers in the PVAT. Plasma concentrations of ICAM1 and IL-17 were increased in WT AIA and hRTN+ / - / - AIA groups compared to control and RTN- / - AIA. Gene expression of M1 and M2 macrophages markers increased in the PVAT of hRTN+/ - / - AIA animals. The absolute number of M1 (F4/80/+CD11c+) increased WT, RTN- / - , hRTN+/ - / - compared to the WT control. However, the absolute number of M2 (F4/80/+CD206+) increased only in WT AIA and hRTN+ / - / - AIA, compared to RTN- / - AIA and control. CAP1 expression was higher in M1 and M2 from hRTN+ / - / - AIA animals compared to the other groups. Therefore, we conclude that human resistin likely via CAP1 promotes PVAT dysfunction by increasing M1 and M2 and amplifying inflammatory mediators, resulting in vascular dysfunction in AIA. (AU) | |
| FAPESP's process: | 19/24921-4 - Role of resistin via CAP1 in perivascular adipose tissue and vascular dysfunction in an experimental Arthritis model |
| Grantee: | Aline Garcia Fedoce |
| Support Opportunities: | Scholarships in Brazil - Doctorate |