The sinoatrial node (SAN) is the primary pacemaker of the mammalian heart. With age, dysfunction of the SAN increases exponentially. We have documented a significant decrease in the intrinsic beating rate (IBR) of young (3-month) and old (24-month) C57Bl mice in last year. This year, we found that the early onset of age associated reduction in the mouse SAN IBR is by 12 months, with no further reduction at older age to 24 months. We hypothesized changes in Ca2+ handling and PKA-dependent signaling might play a significant role in the age-related SAN dysfunction. Our lab has previously shown PDE inhibition not only elevates cAMP concentration in pacemaker cells but also leads to enhanced cAMP mediated-PKA-dependent phosphorylation of Ca2+ cycling proteins as indexed by phospholamban phosphorylation at serene 16 site. Our data shows the inhibition of the degradation of cAMP, by inhibition of degradation by phosphodiesterase using IBMX (Phosphodiesterase inhibitor) can raise the old SANs IBR to comparable levels that occur in the young SANs at high dose of IBMX (1 milli M). However, the IBR of SANs from old mice is less sensitive to IBMX mediated acceleration. The IC50 of IBMX for change in IBR is 2.8 micro M in young SANs (2 month) and 30 micro M in old SANs (20 month) (n=5 in each group, P<0.01). Concomitantly, the preliminary data on single cells dissociated from old SANs shows decreased phospholamban phosphorylation at serine 16 site (PKA site) at basal state and under IBMX stimulation, which is consistent with the decreased sensitivity to IBMX stimulated increase in IBR. The reduced sensitivity to PDE inhibition in SANs from old mice suggests that intrinsic cAMP-PKA signaling is deficient in the old SA node. IBR is critically dependent on cAMP-PKA-signaling, even in the absence of receptor simulation;this reduction in intrinsic cAMP-PKA dependent signaling may result in reduced phosphorylation of Ca2+ cycling proteins. This deficiency is a mechanism for the age associated reduction in IBR.
|Liu, Jie; Sirenko, Syevda; Juhaszova, Magdalena et al. (2014) 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:H1385-97|
|Marine, Joseph E; Shetty, Veena; Chow, Grant V et al. (2013) Prevalence and prognostic significance of exercise-induced nonsustained ventricular tachycardia in asymptomatic volunteers: BLSA (Baltimore Longitudinal Study of Aging). J Am Coll Cardiol 62:595-600|
|Yaniv, Yael; Juhaszova, Magdalena; Sollott, Steven J (2013) Age-related changes of myocardial ATP supply and demand mechanisms. Trends Endocrinol Metab 24:495-505|
|Lakatta, Edward G; Maltsev, Victor A (2012) Rebuttal: what I(f) the shoe doesn't fit? ""The funny current has a major pacemaking role in the sinus node"". Heart Rhythm 9:459-60|
|Bround, Michael J; Asghari, Parisa; Wambolt, Rich B et al. (2012) Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice. Cardiovasc Res 96:372-80|
|Liu, Jie; Sirenko, Syevda; Juhaszova, Magdalena et al. (2011) A full range of mouse sinoatrial node AP firing rates requires protein kinase A-dependent calcium signaling. J Mol Cell Cardiol 51:730-9|
|Lakatta, Edward G; DiFrancesco, Dario (2009) What keeps us ticking: a funny current, a calcium clock, or both? J Mol Cell Cardiol 47:157-70|