Role Of The NLRP3/Inflammasome On Aldosterone‐Induced Vascular Damage

Abstract

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 InformationFinancial 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.