Artículo
Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity
Fernandez Sada, E.; Silva Platas, C.; Villegas, C. A.; Rivero, S. L.; Willis, B. C.; García, N.; Garza, J. R.; Oropeza Almazán, Y.; Valverde, Carlos Alfredo
; Mazzocchi, Gabriela
; Zazueta, C.; Torre Amione, G.; García Rivas, G.
![Icon](/themes/CONICETDigital/images/conicet.png)
![Icon](/themes/CONICETDigital/images/conicet.png)
Fecha de publicación:
09/2014
Editorial:
Wiley
Revista:
British Journal Of Pharmacology
ISSN:
0007-1188
e-ISSN:
1476-5381
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Background and Purpose: Despite the importance of mitochondrial Ca2+ to metabolic regulation and cell physiology, little is known about the mechanisms that regulate Ca2+ entry into the mitochondria. Accordingly, we established a system to determine the role of the mitochondrial Ca2+ uniporter in an isolated heart model, at baseline and during increased workload following β-adrenoceptor stimulation.
Experimental Approach: Cardiac contractility, oxygen consumption and intracellular Ca2+ transients were measured in ex vivo perfused murine hearts. Ru360 and spermine were used to modify mitochondrial Ca2+ uniporter activity. Changes in mitochondrial Ca2+ content and energetic phosphate metabolite levels were determined.
Key Results: The addition of Ru360, a selective inhibitor of the mitochondrial Ca2+ uniporter, induced progressively and sustained negative inotropic effects that were dose-dependent with an EC50 of 7 μM. Treatment with spermine, a uniporter agonist, showed a positive inotropic effect that was blocked by Ru360. Inotropic stimulation with isoprenaline elevated oxygen consumption (2.7-fold), Ca2+-dependent activation of pyruvate dehydrogenase (5-fold) and mitochondrial Ca2+ content (2.5-fold). However, in Ru360-treated hearts, this parameter was attenuated. In addition, β-adrenoceptor stimulation in the presence of Ru360 did not affect intracellular Ca2+ handling, PKA or Ca2+/calmodulin-dependent PK signalling.
Conclusions and Implications: Inhibition of the mitochondrial Ca2+ uniporter decreases β-adrenoceptor response, uncoupling between workload and production of energetic metabolites. Our results support the hypothesis that the coupling of workload and energy supply is partly dependent on mitochondrial Ca2+ uniporter activity.
Palabras clave:
Mitochondria
,
Biochemical Pharmacology
,
Catecholamines
,
Ion Channles
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Articulos(CIC)
Articulos de CENTRO DE INVEST.CARDIOVASCULARES (I)
Articulos de CENTRO DE INVEST.CARDIOVASCULARES (I)
Citación
Fernandez Sada, E.; Silva Platas, C.; Villegas, C. A.; Rivero, S. L.; Willis, B. C.; et al.; Cardiac responses to β-adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity; Wiley; British Journal Of Pharmacology; 171; 18; 9-2014; 4207-4221
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