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Role Of The NLRP3/Inflammasome On Aldosterone‐Induced Vascular Damage
Author(s) -
Nascimento Thiago Bruder,
Ferreira Nathanne,
Zanotto Camila,
Campos Eduardo,
Ramalho Fernanda,
Orlandin Isabela P.,
Olivon Vânia Claudia,
Neves Karla Bianca,
Lopes Rhéure A.M.,
Silva Carlos Alberto,
Carlos Daniela,
Mestriner Fabiola,
AlvesFilho José Carlos,
Cássia Tostes Rita
Publication year - 2016
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.30.1_supplement.1197.8
Subject(s) - inflammasome , medicine , endocrinology , aldosterone , mineralocorticoid receptor , chemistry , inflammation , western blot , apoptosis , mesenteric arteries , vascular smooth muscle , receptor , artery , biochemistry , smooth muscle , gene
Aldosterone (Aldo), a steroid with mineralocorticoid activity, is closely associated with vascular inflammation, remodeling and dysfunction. NLRP3/inflammasome, a member of cytoplasmic NOD‐like receptors, plays important role on inflammatory processes. We postulated that NLRP3/inflammasome mediates aldosterone‐induced vascular damage. To test this hypothesis we analyzed vascular structure and function and inflammatory profile of wild‐type (WT), NLRP3 knockout (NLRP3−/−) and Caspase‐1 knockout ( Casp‐1−/− ) mice treated with vehicle or Aldo (600 ug/kg/day for 14 days, via osmotic mini‐pump) while receiving 1% saline to drink. Aldo infusion did not change the final mean arterial pressure (WT: 101,9 ± 4,8 vs Aldo: 107,4 ± 5,1), but increased plasma levels of IL‐1β (WT: 588,0 ± 103 vs Aldo: 2333,9 ± 658,8* pg/mL, *P<0.05), as well as cleaved caspase‐1 and mature IL‐1β in the mesentery arteries, determined by ELISA and western blot, respectively, in WT mice. Apocynin (antioxidant agent) treatment prevented Aldo‐induced effects. NLRP3−/− and Casp‐1−/− mice were protected against Aldo‐induced vascular changes, i.e. they did not exhibit hypercontractility to phenylephrine [maximal effects (Emax) (WT: 75,2 ± 9,6 vs Aldo: 155,1 ± 22,1* % of KCl‐induced contractility, *P<0.05)] or reduced ACh‐induced relaxation upon Aldo treatment maximal effects [(Emax) (WT: 87,7 ± 2,1 vs Aldo: 34,2 ± 3,3*, % of relaxation, *P<0.05)]. Aldo infusion increased media:lumen ratio and media cross‐sectional area of resistance arteries, augmented RNA expression for inflammatory markers [(ICAM‐1 and VCAM‐1) 3 and 5‐folds, respectively] and the number of adhered macrophages in aortic segments. These Aldo‐induced changes were blunted in NLRP3−/−and Casp‐1−/− mice. To elucidate the role of NLRP3 in the vasculature, we performed bone marrow transplantation (BMT) from WT to NLRP3−/− mice (WTàNLRP3−/−), BMT chimeric mice were protected from Aldo‐induced vascular dysfunction and remodeling. All together these data suggest that NLRP3/inflammasome activation in the vasculature is oxidative stress‐dependent, and plays a crucial role on Aldo‐induced vascular dysfunction and remodeling. Support or Funding Information Financial Support: Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) e Coordenação de Aperfeiçoamento de Ensino Superior 88887.092495/2015‐00 (CAPES), Brazil.