17ß-estradiol induces hyperresponsiveness in guinea pig airway smooth muscle by inhibiting the plasma membrane Ca2+-ATPase
Por:
Romero-Martínez B.S., Flores-Soto E., Sommer B., Reyes-García J., Arredondo-Zamarripa D., Solís-Chagoyán H., Lemini C., Rivero-Segura N.A., Santiago-de-la- Cruz J.A., Pérez-Plascencia C., Montaño L.M.
Publicada:
1 ene 2024
Ahead of Print:
1 may 2024
Resumen:
High serum estrogen concentrations are associated with asthma development and severity, suggesting a link between estradiol and airway hyperresponsiveness (AHR). 17ß-estradiol (E2) has non-genomic effects via Ca2+ regulatory mechanisms; however, its effect on the plasma membrane Ca2+-ATPases (PMCA1 and 4) and sarcoplasmic reticulum Ca2+-ATPase (SERCA) is unknown. Hence, in the present study, we aim to demonstrate if E2 favors AHR by increasing intracellular Ca2+ concentrations in guinea pig airway smooth muscle (ASM) through a mechanism involving Ca2+-ATPases. In guinea pig ASM, Ca2+ microfluorometry, muscle contraction, and Western blot were evaluated. Then, we performed molecular docking analysis between the estrogens and Ca2+ ATPases. In tracheal rings, E2 produced AHR to carbachol. In guinea pig myocytes, acute exposure to physiological levels of E2 modified the transient Ca2+ peak induced by caffeine to a Ca2+ plateau. The incubation with PMCA inhibitors (lanthanum and carboxyeosin, CE) partially reversed the E2-induced sustained plateau in the caffeine response. In contrast, cyclopiazonic acid (SERCA inhibitor), U-0126 (an inhibitor of ERK 1/2), and choline chloride did not modify the Ca2+ plateau produced by E2. The mitochondrial uniporter activity and the capacitative Ca2+ entry were unaffected by E2. In guinea pig ASM, Western blot analysis demonstrated PMCA1 and PMCA4 expression. The results from the docking modeling demonstrate that E2 binds to both plasma membrane ATPases. In guinea pig tracheal smooth muscle, inhibiting the PMCA with CE, induced hyperresponsiveness to carbachol. 17ß-estradiol produces hyperresponsiveness by inhibiting the PMCA in the ASM and could be one of the mechanisms responsible for the increase in asthmatic crisis in women. © 2024 Elsevier B.V.
Filiaciones:
Romero-Martínez B.S.:
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Alcaldía de Coyoacán, CDMX, 04510, CP, Mexico
Flores-Soto E.:
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Alcaldía de Coyoacán, CDMX, 04510, CP, Mexico
Sommer B.:
Departamento de Investigación en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias, Calz. De Tlalpan 4502, Col. Sección XVI, Alcaldía de Tlalpan, CDMX, 14080, CP, Mexico
Reyes-García J.:
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Alcaldía de Coyoacán, CDMX, 04510, CP, Mexico
Arredondo-Zamarripa D.:
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Alcaldía de Coyoacán, CDMX, 04510, CP, Mexico
Solís-Chagoyán H.:
Neurociencia Cognitiva Evolutiva, Centro de Investigación en Ciencias Cognitivas, Universidad Autónoma Del Estado de Morelos, Morelos, CP 62209, Mexico
Lemini C.:
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Alcaldía de Coyoacán, CDMX, 04510, CP, Mexico
Rivero-Segura N.A.:
Dirección de Investigación, Instituto Nacional de Geriatría (INGER), Ciudad de México, 10200, CP, Mexico
Santiago-de-la- Cruz J.A.:
Dirección de Investigación, Instituto Nacional de Geriatría (INGER), Ciudad de México, 10200, CP, Mexico
Pérez-Plascencia C.:
Unidad de Genómica y Cáncer, Subdirección de Investigación Básica, INCan, SSA, Av. San Fernando 22, Alcaldía de Tlalpan, CDMX, 14080, CP, Mexico
Facultad de Estudios Superiores Iztacala, Av. de Los Barrios S/N Los Reyes Ixtacala Tlalnepantla de Baz, Edo. de México, Tlalnepantla de Baz, 54090, CP, Mexico
Montaño L.M.:
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Alcaldía de Coyoacán, CDMX, 04510, CP, Mexico
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