NLRP3 Inflammasome and Mineralocorticoid Receptors Are Associated with Vascular Dysfunction in Type 2 Diabetes Mellitus

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Ferreira, Nathanne Santos ^[1] ; Bruder-Nascimento, Thiago ^[1] ; Pereira, Camila Andre ^[1] ; Zanotto, Camila Zillioto ^[1] ; Prado, Douglas Silva ^[1] ; Silva, Josiane Fernandes ^[1] ; Rassi, Diane Meyre ^[1] ; Foss-Freitas, Maria Cristina ^[2] ; Alves-Filho, Jose Carlos ^{[1, 3]} ; Carlos, Daniela ^[3] ; Tostes, Rita de Cassia ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, BR-14040900 Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Clin Med, BR-14040900 Ribeirao Preto - Brazil

^[3] Univ Sao Paulo, Dept Biochem & Immunol, Ribeirao Preto Med Sch, BR-14040900 Ribeirao Preto - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CELLS; v. 8, n. 12 DEC 2019.
• Citações Web of Science: 0

Resumo

Aldosterone excess aggravates endothelial dysfunction in diabetes and hypertension by promoting the increased generation of reactive oxygen species, inflammation, and insulin resistance. Aldosterone activates the molecular platform inflammasome in immune system cells and contributes to vascular dysfunction induced by the mineralocorticoid hormone. It is unclear as to whether the NLRP3 inflammasome associated with the mineralocorticoid receptor contributes to vascular dysfunction in diabetic conditions. Here, we tested the hypothesis that an excess of aldosterone induces vascular dysfunction in type 2 diabetes, via the activation of mineralocorticoid receptors (MR) and assembly of the NLRP3 inflammasome. Mesenteric resistance arteries from control (db/m) and diabetic (db/db) mice treated with vehicle, spironolactone (MR antagonist) or an NLRP3 selective inhibitor (MCC950) were used to determine whether NLRP3 contributes to diabetes-associated vascular dysfunction. Db/db mice exhibited increased vascular expression/activation of caspase-1 and IL-1 beta, increased plasma IL-1 beta levels, active caspase-1 in peritoneal macrophages, and reduced acetylcholine (ACh) vasodilation, compared to db/m mice. Treatment of db/db mice with spironolactone and MCC950 decreased plasma IL-1 beta and partly restored ACh vasodilation. Spironolactone also reduced active caspase-1-positive macrophages in db/db mice, events that contribute to diabetes-associated vascular changes. These data clearly indicate that MR and NLRP3 activation contribute to diabetes-associated vascular dysfunction and pro-inflammatory phenotype. (AU)

• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs