CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation
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CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation. / Neef, Stefan; Dybkova, Nataliya; Sossalla, Samuel; Ort, Katharina R; Fluschnik, Nina; Neumann, Kay; Seipelt, Ralf; Schöndube, Friedrich A; Hasenfuss, Gerd; Maier, Lars S.
in: CIRC RES, Jahrgang 106, Nr. 6, 02.04.2010, S. 1134-1144.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation
AU - Neef, Stefan
AU - Dybkova, Nataliya
AU - Sossalla, Samuel
AU - Ort, Katharina R
AU - Fluschnik, Nina
AU - Neumann, Kay
AU - Seipelt, Ralf
AU - Schöndube, Friedrich A
AU - Hasenfuss, Gerd
AU - Maier, Lars S
PY - 2010/4/2
Y1 - 2010/4/2
N2 - RATIONALE: Although research suggests that diastolic Ca(2+) levels might be increased in atrial fibrillation (AF), this hypothesis has never been tested. Diastolic Ca(2+) leak from the sarcoplasmic reticulum (SR) might increase diastolic Ca(2+) levels and play a role in triggering or maintaining AF by transient inward currents through Na(+)/Ca(2+) exchange. In ventricular myocardium, ryanodine receptor type 2 (RyR2) phosphorylation by Ca(2+)/calmodulin-dependent protein kinase (CaMK)II is emerging as an important mechanism for SR Ca(2+) leak.OBJECTIVE: We tested the hypothesis that CaMKII-dependent diastolic SR Ca(2+) leak and elevated diastolic Ca(2+) levels occurs in atrial myocardium of patients with AF.METHODS AND RESULTS: We used isolated human right atrial myocytes from patients with AF versus sinus rhythm and found CaMKII expression to be increased by 40+/-14% (P<0.05), as well as CaMKII phosphorylation by 33+/-12% (P<0.05). This was accompanied by a significantly increased RyR2 phosphorylation at the CaMKII site (Ser2814) by 110+/-53%. Furthermore, cytosolic Ca(2+) levels were elevated during diastole (229+/-20 versus 164+/-8 nmol/L, P<0.05). Most likely, this resulted from an increased SR Ca(2+) leak in AF (P<0.05), which was not attributable to higher SR Ca(2+) load. Tetracaine experiments confirmed that SR Ca(2+) leak through RyR2 leads to the elevated diastolic Ca(2+) level. CaMKII inhibition normalized SR Ca(2+) leak and cytosolic Ca(2+) levels without changes in L-type Ca(2+) current.CONCLUSION: Increased CaMKII-dependent phosphorylation of RyR2 leads to increased SR Ca(2+) leak in human AF, causing elevated cytosolic Ca(2+) levels, thereby providing a potential arrhythmogenic substrate that could trigger or maintain AF.
AB - RATIONALE: Although research suggests that diastolic Ca(2+) levels might be increased in atrial fibrillation (AF), this hypothesis has never been tested. Diastolic Ca(2+) leak from the sarcoplasmic reticulum (SR) might increase diastolic Ca(2+) levels and play a role in triggering or maintaining AF by transient inward currents through Na(+)/Ca(2+) exchange. In ventricular myocardium, ryanodine receptor type 2 (RyR2) phosphorylation by Ca(2+)/calmodulin-dependent protein kinase (CaMK)II is emerging as an important mechanism for SR Ca(2+) leak.OBJECTIVE: We tested the hypothesis that CaMKII-dependent diastolic SR Ca(2+) leak and elevated diastolic Ca(2+) levels occurs in atrial myocardium of patients with AF.METHODS AND RESULTS: We used isolated human right atrial myocytes from patients with AF versus sinus rhythm and found CaMKII expression to be increased by 40+/-14% (P<0.05), as well as CaMKII phosphorylation by 33+/-12% (P<0.05). This was accompanied by a significantly increased RyR2 phosphorylation at the CaMKII site (Ser2814) by 110+/-53%. Furthermore, cytosolic Ca(2+) levels were elevated during diastole (229+/-20 versus 164+/-8 nmol/L, P<0.05). Most likely, this resulted from an increased SR Ca(2+) leak in AF (P<0.05), which was not attributable to higher SR Ca(2+) load. Tetracaine experiments confirmed that SR Ca(2+) leak through RyR2 leads to the elevated diastolic Ca(2+) level. CaMKII inhibition normalized SR Ca(2+) leak and cytosolic Ca(2+) levels without changes in L-type Ca(2+) current.CONCLUSION: Increased CaMKII-dependent phosphorylation of RyR2 leads to increased SR Ca(2+) leak in human AF, causing elevated cytosolic Ca(2+) levels, thereby providing a potential arrhythmogenic substrate that could trigger or maintain AF.
KW - Action Potentials
KW - Anesthetics, Local/pharmacology
KW - Atrial Fibrillation/enzymology
KW - Benzylamines/pharmacology
KW - Calcium Channels, L-Type/metabolism
KW - Calcium Signaling/drug effects
KW - Calcium-Binding Proteins/metabolism
KW - Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors
KW - Case-Control Studies
KW - Cell Size
KW - Diastole
KW - Heart Atria/enzymology
KW - Humans
KW - Microscopy, Confocal
KW - Myocardium/enzymology
KW - Patch-Clamp Techniques
KW - Phosphorylation
KW - Protein Kinase Inhibitors/pharmacology
KW - Ryanodine Receptor Calcium Release Channel/metabolism
KW - Sarcoplasmic Reticulum/drug effects
KW - Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism
KW - Sodium-Calcium Exchanger/metabolism
KW - Sulfonamides/pharmacology
KW - Systole
KW - Tetracaine/pharmacology
KW - Time Factors
KW - Up-Regulation
U2 - 10.1161/CIRCRESAHA.109.203836
DO - 10.1161/CIRCRESAHA.109.203836
M3 - SCORING: Journal article
C2 - 20056922
VL - 106
SP - 1134
EP - 1144
JO - CIRC RES
JF - CIRC RES
SN - 0009-7330
IS - 6
ER -