Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca²⁺signaling

Abstract

Lakatta EG. Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca 2ϩ signaling. Am J Physiol Heart Circ Physiol 306: H1385-H1397, 2014. First published March 14, 2014 doi:10.1152/ajpheart.00088.2014.-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 2ϩ clock, and the electrogenic-sarcolemmal membrane clock. Ca 2ϩ -activated-calmodulin-adenylyl cyclase/CaMKII-cAMP/PKA-Ca 2ϩ signaling regulated by phosphodiesterase activity drives SAN cells automaticity. SR-generated local calcium releases (LCRs) activate Na ϩ /Ca 2ϩ 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 2ϩ 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 2ϩ -cycling proteins, including SR Ca 2ϩ -ATPase pump, ryanodine receptors, and Na ϩ /Ca 2ϩ exchanger. Thus a deterioration in intrinsic Ca 2ϩ clock kinetics in aged SAN cells, due to deficits in intrinsic SR Ca 2ϩ 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.aging; Ca 2ϩ transient; intrinsic heart rate; pacemaker function; PKA signaling AN AGE-ASSOCIATED REDUCTION in heart rate acceleration in response to stress is a major factor underlying the age-associated decline in cardiovascular reserve (29). Specifically, the heart rate increase in response to perturbations from the supine basal state, e.g., on assuming an upright posture or during exercise, is reduced in older vs. younger persons (43). That an exaggerated increase in plasma catecholamines accompanies the reduction in heart rate reserve in older persons suggests that the age-associated reduction in heart rate reserve, in part at least, is attributable to postsynaptic mechanisms that reside within the sinoatrial node (SAN) (14). Broadly, these postsynaptic mechanisms include intrinsic mechanisms that control the rate and rhythm of spontaneous action potential (AP) firing of SAN pacemaker cells, and autonomic receptor signaling that modulates these intrinsic pacemaker cell mechanisms (3, 22, 37). The...

The impacts of age and frailty on heart rate and sinoatrial node function

“…; Liu et al . ). Reduction in these currents is consistent with the reductions in DD slope and AP duration, as well as the slowing of SAN CV we have observed in our study.…”

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“…Mechanisms that underlie the age-associated reduction in peak heart rate and ejection fraction are multifactorial and include a reduction in intrinsic sinoatrial pacemaker cell function [45; cf. 46 in this volume] and ventricular myocyte intrinsic contractility [43; also cf.…”

“…Substantial evidence points to the reduced efficiency of postsynaptic beta-adrenergic signaling with aging [43 for review]. Thus, cardiovascular responses including those of pacemaker tissue [45] to beta-adrenergic agonist infusions at rest decrease with age, and acute beta-adrenergic receptor blockade changes the exercise hemodynamic profile of younger persons to make it resemble that of older individuals. During exercise the heart rate reduction by acute beta-adrenergic blockade is greater in younger versus older subjects, as are the age-associated deficits in LV early diastolic filling rate, both at rest and during exercise.…”

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“…Despite recent advances in redox biology and aging research (9,21,27,33,37,49,51,52,55,59,65,72,97), the role of ROS in the cerebromicrovascular effects of CR remains elusive. To assess cellular peroxide production, we used the cell-permeant oxidative fluorescent indicator dye CM-H 2DCFDA [5 (and 6)-chloromethyl-2=,7=-dichlorodihydrofluorescein diacetateacetyl ester; Invitrogen, Carlsbad, CA] as we previously reported (16,86).…”