Abstract
Ca$^2+$ in cardiac myocytes regulates contractility and relaxation,
and Ca$^2+$ and Na$^+$ regulation are linked via Na$^+$/Ca$^2+$
exchange (NCX). Heart failure (HF) is accompanied by contractile
dysfunction and arrhythmias, both of which may be due to altered
cellular Ca$^2+$ handling. Smaller Ca$^2+$ transient and
sarcoplasmic reticulum (SR) Ca$^2+$ content cause systolic dysfunction
in HF. The reduced SR Ca$^2+$ content is due to: (a) reduced
SR Ca$^2+$-ATPase function (which also contributes to diastolic
dysfunction), (b) increased expression and function of NCX (which
competes with SR Ca$^2+$-ATPase during relaxation, but preserves
diastolic function), and (c) enhanced diastolic SR Ca$^2+$ leak.
Relative contributions of these may vary with HF etiology and stage.
Triggered arrhythmias (e.g., delayed afterdepolarizations DADs)
are prominent in HF. DADs are due to spontaneous SR Ca$^2+$ release
and consequent activation of transient inward NCX current, which
in HF allows DADs to more readily trigger arrhythmogenic action potentials.
Thus NCX and Na$^+$ are critical in systolic and diastolic function
and arrhythmias. Na$^+$(i) is elevated in HF, which may limit
SR unloading and provide some Ca$^2+$ influx during the HF action
potential, thus limiting the depression of systolic function. High
Na$^+$(i) in HF is due to enhanced Na$^+$ influx. Cellular
Na$^+$/K$^+$-ATPase (NKA) function appears unaltered, despite
reduced NKA expression. This dichotomy led us to test NKA regulation
by phospholemman (PLM). We find that PLM regulates NKA in a manner
analogous to phospholamban regulation of SR Ca$^2+$-ATPase (i.e.,
inhibition that is relieved by PLM phosphorylation). We measured
intermolecular FRET between PLM and NKA, which is reduced upon PLM
phosphorylation. The lower expression level of more phosphorylated
PLM in HF may explain the above dichotomy. Thus, altered Ca$^2+$
and Na$^+$ handling contributes to altered contractile function
and arrhythmogenesis in HF.
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