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.2012 Jun 15;302(12):C1762-71.
doi: 10.1152/ajpcell.00425.2011. Epub 2012 Apr 11.

Ablation of sarcolipin results in atrial remodeling

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Ablation of sarcolipin results in atrial remodeling

Lai-Hua Xie et al. Am J Physiol Cell Physiol..

Abstract

Sarcolipin (SLN) is a key regulator of sarco(endo)plasmic reticulum (SR) Ca(2+)-ATPase (SERCA), and its expression is altered in diseased atrial myocardium. To determine the precise role of SLN in atrial Ca(2+) homeostasis, we developed a SLN knockout (sln-/-) mouse model and demonstrated that ablation of SLN enhances atrial SERCA pump activity. The present study is designed to determine the long-term effects of enhanced SERCA activity on atrial remodeling in the sln-/- mice. Calcium transient measurements show an increase in atrial SR Ca(2+) load and twitch Ca(2+) transients. Patch-clamping experiments demonstrate activation of the forward mode of sodium/calcium exchanger, increased L-type Ca(2+) channel activity, and prolongation of action potential duration at 90% repolarization in the atrial myocytes of sln-/- mice. Spontaneous Ca(2+) waves, delayed afterdepolarization, and triggered activities are frequent in the atrial myocytes of sln-/- mice. Furthermore, loss of SLN in atria is associated with increased interstitial fibrosis and altered expression of genes encoding collagen and other extracellular matrix proteins. Our results also show that the sln-/- mice are susceptible to atrial arrhythmias upon aging. Together, these findings indicate that ablation of SLN results in increased SERCA activity and SR Ca(2+) load, which, in turn, could cause abnormal intracellular Ca(2+) handling and atrial remodeling.

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Figures

Fig. 1.
Fig. 1.
Ca2+ transient amplitude and sarco(endo)plasmic reticulum (SR) Ca2+ content in sarcolipin knockout (sln−/−) atrial myocytes.A: twitch Ca2+ transients elicited by field stimulation at 0.5 Hz, and Ca2+ content measured as the height of the caffeine (Caff; 10 mmol/l)-induced Ca2+ transient in a representative atrial myocyte from wild-type (WT) andsln−/− mice. Ca2+ fluorescence intensity was recorded as the ratio F/F0 of the fluorescence (F) over the basal diastolic fluorescence (F0).B: summarized data for twitch Ca2+ transient in atrial myocytes.C: summarized data for SR Ca2+ contents in WT andsln−/− atrial myocytes.D: summarized data for fractional SR Ca2+ release, calculated by dividing the height of the last twitch transient by the height of the Caff transient. Values are means ± SE; no. of cells analyzed is indicated above each bar. **P < 0.05 compared with WT control myocytes. ns, Not significant.
Fig. 2.
Fig. 2.
Alternations of action potential (AP) morphology, occurrences of delayed afterdepolarizations (DADs), triggered activities, and spontaneous Ca2+ release in the atrial myocytes ofsln−/− mice.A: representative AP recordings from the atrial myocytes of WT andsln−/− mice. Note the apparent late plateau phase in the AP recorded fromsln−/− atrial myocyte.B: summary of AP duration (APD) values. The APD at 90% repolarization (APD90) is prolonged in atrial myocytes ofsln−/− mice.C: comparison of the effects of Na+-free, Li+-containing Tyrode's solution on the AP properties, especially the late plateau insln−/− and WT mice atrial myocytes.D: DAD (*) and triggered activities (↓) appear in atrial myocytes fromsln−/− mice.E: representative traces of intracellular Ca2+ concentration fluorescence from WT andsln−/− atrial myocyte showing different incidences of spontaneous Ca2+ release (4 cells for each).F: percentage of oscillating atrial cells with spontaneous Ca2+ release in thesln−/− and WT mice. Values are means ± SE; no. of cells analyzed is indicated above each bar. **Significantly different from the WT atrial myocytes,P < 0.05 by Fisher's exact test.
Fig. 3.
Fig. 3.
L-type Ca2+ current (ICa,L), Na+/Ca2+ exchange current (INCX), and total outward K currents in thesln−/− atrial myocytes.A: representative current-voltage curve.B:ICa,L traces elicited at testing potential of 0 mV.C: summary ofICa,L densities.D: representative traces elicited with the voltage-clamp protocol shown.E: peak K currents at test potential of +40 mV in WT andsln−/− atrial myocytes.IK,total, total K current.F: representative tracings of Ca2+ transients (top) andINCX (bottom) after rapid application of Caff in atrial myocytes isolated fromsln−/− or WT control hearts.G: average values of peak Ca2+ transient (F/F0,top) and peakINCX densities (bottom). Values are means ± SE; no. of cells analyzed is indicated above each bar. **P < 0.05; ***P < 0.01,sln−/− vs WT.
Fig. 4.
Fig. 4.
Western blot analysis of Ca2+ handling proteins in thesln−/− mice atria.A: Western blots showing the protein levels of SR Ca2+-ATPase (SERCA) 2a, calsequestrin (CSQ), NCX, dihydropyridine receptor (DHPR-α), phospholamban (PLN), and ryanodine receptor (RyR).B: the fold change in expression levels of these proteins. The expression levels are normalized to CSQ levels.C: the ratios of serine 16 phosphorylated PLN (PS16-PLN) to total PLN and serine 2808 or 2814 phosphorylated RyR to total RyR;n = 3. Values are means ± SE. *Significantly different from the WT mice atria,P < 0.01.
Fig. 5.
Fig. 5.
Increased interstitial fibrosis in thesln−/− atria.A: representative images showing the Picro Sirius Red staining of atrial tissues from 5-mo-old WT andsln−/− mice. Original magnifications ×400. Bar represents 20 μm. Arrow indicates the collagen accumulation between the fibers.B: quantitation of Sirius Red stained connective tissue in atria of WT andsln−/− mice. Values are means ± SE;n = 5. *P < 0.0001.
Fig. 6.
Fig. 6.
Genomewide analysis of gene expression regulation insln−/− atria.A: comparative analysis of significantly regulated genes in atria ofsln−/− mice (GEO accession no. GSE23403) vs. those in human patients with atrial fibrillation (AF) (GEO accession no. GSE2240). Significant genes were selected using cutoffs of fold change of 1.2 and 5% false discovery rate (significant analysis of microarrays). AP value (χ2 test) indicating significance of the numbers of overlapped genes is shown in the graph. *Statistically overrepresented.B: quantitative RT-PCR analyses of selected genes. BMP, bone morphogenetic protein; Cyst9, cystatin 9; Cx40, connexin 40; Timp4, tissue inhibitor of MMP4; CathK, cathepsin K; MMP3, matrix metalloproteinase 3. Values are means ± SE;n = 5. *Significant difference vs. WT,P < 0.05.
Fig. 7.
Fig. 7.
ECG recordings of 12-mo-oldsln−/− mice. Representative surface ECG lead II recordings from 12-mo-old WT (A) andsln−/− (B andC) mice are shown. Arrows indicate the P waves.
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