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Oxidative stress and unfolded protein response (UPR) in advanced aortic disease from Marfan Syndrome (MFS) transgenic mice
Author(s) -
Guido Maria Carolina,
Salemi Vera,
Takimura Celso,
Debbas Victor,
Pereira Lygia da Veiga,
Laurindo Francisco Rafafel Martins
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb609
Subject(s) - adventitia , protein disulfide isomerase , oxidative stress , chemistry , aorta , heat shock protein , unfolded protein response , aortic aneurysm , fibrillin , reactive oxygen species , medicine , endocrinology , extracellular matrix , biochemistry , endoplasmic reticulum , gene
We investigated the occurrence and mechanisms of oxidative stress in aortae from MFS mouse model (mgÄFBN1). Aortic dilation, elastic fiber rupture and collagen deposition markedly increased from 3–6 months(mo). ROS production (by 3 methods) increased in aortae from 6‐mo, but not 1 or 3‐mo‐old MFS mice, mainly at crossa. Nox4 mRNA increased after 1mo, while Nox2 only at 6mo. To assess oxidative stress mechanisms, we investigated UPR markers in MFS aortae. Expression of KDEL chaperones increased at 6mo, but not 1 or 3mo. Protein disulfide isomerase(PDI), which associates with and regulates Nox(es), equally increased. Also, PDI expression topography correlated with ROS production sites (DMPO adduct antibody), mainly at adventitia in crossa and media in abdominal aorta. Adventitial PDI switch in crossa correlated with diffuse collagen accumulation. Moreover, yeast‐two‐hybrid screening disclosed PDI interaction with fibrillin‐1(FBN1); in cultured fibroblasts, such association was mainly intra, but not extracellular. FBN1 immunodetection decreased by~80% and co‐localized with PDI in MFS adventitia. PDI/UPR marker changes were not systemic and absent in kidney and liver. Losartan prevented aortic remodeling, but ROS production remained increased in aorta at 6mo. Thus, ROS production increases with MFS aortic disease progression, in close temporal and topographic correlation with PDI expression and UPR.