Small artery remodeling and stiffening in deoxycorticosterone acetate-salt hypertensive rats involves the interaction between endogenous ouabain/Na⁺K⁺-ATPase/cSrc signaling

Autor(es)

Tomazelli, Caroline Aparecida ; Ishikawa, Flavia Midori ; Couto, Gisele Kruger ; Parente, Juliana Montenegro ; de Castro, Michele Mazzaron ; Xavier, Fabiano Elias ; Rossoni, Luciana Venturini

• Tipo de documento: Artigo Científico
• Fonte: Journal of Hypertension; v. 41, n. 10, p. 11-pg., 2023-10-01.

Resumo

Objective: Endogenous ouabain (EO) increases in some patients with hypertension and in rats with volumedependent hypertension. When ouabain binds to N+ K+ -ATPase, cSrc is activated, which leads to multieffector signaling activation and high blood pressure (BP). In mesenteric resistance arteries (MRA) from deoxycorticosterone acetate (DOCA)-salt rats, we have demonstrated that the EO antagonist rostafuroxin blocks downstream cSrc activation, enhancing endothelial function and lowering oxidative stress and BP. Here, we examined the possibility that EO is involved in the structural and mechanical alterations that occur in MRA from DOCA-salt rats. Methods: MRA were taken from control, vehicle-treated DOCA-salt or rostafuroxin (1 mg/kg per day, for 3 weeks)-treated DOCA-salt rats. Pressure myography and histology were used to evaluate the mechanics and structure of the MRA, and western blotting to assess protein expression. Results: DOCA-salt MRA exhibited signs of inward hypertrophic remodeling and increased stiffness, with a higher wall:lumen ratio, which were reduced by rostafuroxin treatment. The enhanced type I collagen, TGFb1, pSmad2/3(Ser465/457)/Smad2/3 ratio, CTGF, p-Src(Tyr418), EGFR, c-Raf, ERK1/2 and p38MAPK protein expression in DOCA-salt MRA were all recovered by rostafuroxin. Conclusion: A process combining Na+ K+ -ATPase/cSrc/ EGFR/Raf/ERK1/2/p38MAPK activation and a Na+ K+ -ATPase/cSrc/TGF-1/Smad2/3/CTGF-dependent mechanism explains how EO contributes to small artery inward hypertrophic remodeling and stiffening in DOCA-salt rats. This result supports the significance of EO as a key mediator for end-organ damage in volume-dependent hypertension and the efficacy of rostafuroxin in avoiding remodeling and stiffening of small arteries. (AU)

• Processo FAPESP: 19/08026-5 - Ajustes da inervação perivascular e do remodelamento em artéria de resistência do modelo de hipertensão arterial DOCA-sal: participação da ouabaína endógena
• Beneficiário: Luciana Venturini Rossoni
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/18828-3 - Avaliação dos efeitos da amamentação cruzada sobre os parâmetros mecânicos e estruturais de artérias mesentéricas de resistência em ratos hipertensos e normotensos
• Beneficiário: Flávia Midori Ishikawa
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica