Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca(2+) signaling.
Am J Physiol Heart Circ Physiol
; 306(10): H1385-97, 2014 May 15.
Article
em En
| MEDLINE
| ID: mdl-24633551
ABSTRACT
A reduced sinoatrial node (SAN) functional reserve underlies the age-associated decline in heart rate acceleration in response to stress. SAN cell function involves an oscillatory coupled-clock system the sarcoplasmic reticulum (SR), a Ca(2+) clock, and the electrogenic-sarcolemmal membrane clock. Ca(2+)-activated-calmodulin-adenylyl cyclase/CaMKII-cAMP/PKA-Ca(2+) signaling regulated by phosphodiesterase activity drives SAN cells automaticity. SR-generated local calcium releases (LCRs) activate Na(+)/Ca(2+) exchanger in the membrane clock, which initiates the action potential (AP). We hypothesize that SAN cell dysfunctions accumulate with age. We found a reduction in single SAN cell AP firing in aged (20-24 mo) vs. adult (3-4 mo) mice. The sensitivity of the SAN beating rate responses to both muscarinic and adrenergic receptor activation becomes decreased in advanced age. Additionally, age-associated coincident dysfunctions occur stemming from compromised clock functions, including a reduced SR Ca(2+) load and a reduced size, number, and duration of spontaneous LCRs. Moreover, the sensitivity of SAN beating rate to a cAMP stress induced by phosphodiesterase inhibitor is reduced, as are the LCR size, amplitude, and number in SAN cells from aged vs. adult mice. These functional changes coincide with decreased expression of crucial SR Ca(2+)-cycling proteins, including SR Ca(2+)-ATPase pump, ryanodine receptors, and Na(+)/Ca(2+) exchanger. Thus a deterioration in intrinsic Ca(2+) clock kinetics in aged SAN cells, due to deficits in intrinsic SR Ca(2+) cycling and its response to a cAMP-dependent pathway activation, is involved in the age-associated reduction in intrinsic resting AP firing rate, and in the reduction in the acceleration of heart rate during exercise.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Nó Sinoatrial
/
Envelhecimento
/
Transdução de Sinais
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Cálcio
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Proteínas Quinases Dependentes de AMP Cíclico
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AMP Cíclico
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article