CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation

TY - JOUR

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 -