Inhibition of elevated Ca2+/calmodulin-dependent protein kinase II improves contractility in human failing myocardium

TY - JOUR

T1 - Inhibition of elevated Ca2+/calmodulin-dependent protein kinase II improves contractility in human failing myocardium

AU - Sossalla, Samuel

AU - Fluschnik, Nina

AU - Schotola, Hanna

AU - Ort, Katharina R

AU - Neef, Stefan

AU - Schulte, Timo

AU - Wittköpper, Katrin

AU - Renner, André

AU - Schmitto, Jan D

AU - Gummert, Jan

AU - El-Armouche, Ali

AU - Hasenfuss, Gerd

AU - Maier, Lars S

PY - 2010/10/29

Y1 - 2010/10/29

N2 - RATIONALE: Heart failure (HF) is known to be associated with increased Ca(2+)/calmodulin-dependent protein kinase (CaMK)II expression and activity. There is still controversial discussion about the functional role of CaMKII in HF. Moreover, CaMKII inhibition has never been investigated in human myocardium.OBJECTIVE: We sought to investigate detailed CaMKIIδ expression in end-stage failing human hearts (dilated and ischemic cardiomyopathy) and the functional effects of CaMKII inhibition on contractility.METHODS AND RESULTS: Expression analysis revealed that CaMKIIδ, both cytosolic δ(C) and nuclear δ(B) splice variants, were significantly increased in both right and left ventricles from patients with dilated or ischemic cardiomyopathy versus nonfailing. Experiments with isometrically twitching trabeculae revealed significantly improved force frequency relationships in the presence of CaMKII inhibitors (KN-93 and AIP). Increased postrest twitches after CaMKII inhibition indicated an improved sarcoplasmic reticulum (SR) Ca(2+) loading. This was confirmed in isolated myocytes by a reduced SR Ca(2+) spark frequency and hence SR Ca(2+) leak, resulting in increased SR Ca(2+) load when inhibiting CaMKII. Ryanodine receptor type 2 phosphorylation at Ser2815, which is known to be phosphorylated by CaMKII thereby contributing to SR Ca(2+) leak, was found to be markedly reduced in KN-93-treated trabeculae. Interestingly, CaMKII inhibition did not influence contractility in nonfailing sheep trabeculae.CONCLUSIONS: The present study shows for the first time that CaMKII inhibition acutely improves contractility in human HF where CaMKIIδ expression is increased. The mechanism proposed consists of a reduced SR Ca(2+) leak and consequently increased SR Ca(2+) load. Thus, CaMKII inhibition appears to be a possible therapeutic option for patients with HF and merits further investigation.

AB - RATIONALE: Heart failure (HF) is known to be associated with increased Ca(2+)/calmodulin-dependent protein kinase (CaMK)II expression and activity. There is still controversial discussion about the functional role of CaMKII in HF. Moreover, CaMKII inhibition has never been investigated in human myocardium.OBJECTIVE: We sought to investigate detailed CaMKIIδ expression in end-stage failing human hearts (dilated and ischemic cardiomyopathy) and the functional effects of CaMKII inhibition on contractility.METHODS AND RESULTS: Expression analysis revealed that CaMKIIδ, both cytosolic δ(C) and nuclear δ(B) splice variants, were significantly increased in both right and left ventricles from patients with dilated or ischemic cardiomyopathy versus nonfailing. Experiments with isometrically twitching trabeculae revealed significantly improved force frequency relationships in the presence of CaMKII inhibitors (KN-93 and AIP). Increased postrest twitches after CaMKII inhibition indicated an improved sarcoplasmic reticulum (SR) Ca(2+) loading. This was confirmed in isolated myocytes by a reduced SR Ca(2+) spark frequency and hence SR Ca(2+) leak, resulting in increased SR Ca(2+) load when inhibiting CaMKII. Ryanodine receptor type 2 phosphorylation at Ser2815, which is known to be phosphorylated by CaMKII thereby contributing to SR Ca(2+) leak, was found to be markedly reduced in KN-93-treated trabeculae. Interestingly, CaMKII inhibition did not influence contractility in nonfailing sheep trabeculae.CONCLUSIONS: The present study shows for the first time that CaMKII inhibition acutely improves contractility in human HF where CaMKIIδ expression is increased. The mechanism proposed consists of a reduced SR Ca(2+) leak and consequently increased SR Ca(2+) load. Thus, CaMKII inhibition appears to be a possible therapeutic option for patients with HF and merits further investigation.

KW - Animals

KW - Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors

KW - Cells, Cultured

KW - Heart Failure/drug therapy

KW - Humans

KW - Myocardial Contraction/drug effects

KW - Myocardium/enzymology

KW - Protein Kinase Inhibitors/pharmacology

KW - Sheep

U2 - 10.1161/CIRCRESAHA.110.220418

DO - 10.1161/CIRCRESAHA.110.220418

M3 - SCORING: Journal article

C2 - 20814023

VL - 107

SP - 1150

EP - 1161

JO - CIRC RES

JF - CIRC RES

SN - 0009-7330

IS - 9

ER -