Inhibition of Elevated Ca2+/Calmodulin-Dependent Protein Kinase II Improves Contractility in Human Failing Myocardium

• Published in: Circulation research Vol. 107; no. 9; pp. 1150 - 1161
• Main Authors: Sossalla, Samuel, Fluschnik, Nina, Schotola, Hanna, Ort, Katharina R, Neef, Stefan, Schulte, Timo, Wittköpper, Katrin, Renner, André, Schmitto, Jan D, Gummert, Jan, El-Armouche, Ali, Hasenfuss, Gerd, Maier, Lars S
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 29.10.2010; Lippincott Williams & Wilkins
• Subjects: Animals; Biological and medical sciences; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - biosynthesis; Cardiology. Vascular system; Cells, Cultured; Fundamental and applied biological sciences. Psychology; Heart; Heart Failure - drug therapy; Heart Failure - enzymology; Heart Failure - physiopathology; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Humans; Medical sciences; Myocardial Contraction - drug effects; Myocardial Contraction - physiology; Myocardium - enzymology; Myocardium - pathology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Sheep; Vertebrates: cardiovascular system; Human; Heart failure; calmodulin-dependent protein kinase; Calcium; Enzyme; Transferases; Contractility; Ryanodine receptor; Cardiovascular disease; Inorganic element; leak; Vertebrata; Mammalia; sarcoplasmic reticulum Ca; Sarcoplasmic reticulum; Heart disease; Myocardium; calmodulin-dependent kinase II; Circulatory system; Inhibition; Ca
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.110.220418

RATIONALE:Heart failure (HF) is known to be associated with increased Ca/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 δC and nuclear δB 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 loading. This was confirmed in isolated myocytes by a reduced SR Ca spark frequency and hence SR Ca leak, resulting in increased SR Ca load when inhibiting CaMKII. Ryanodine receptor type 2 phosphorylation at Ser2815, which is known to be phosphorylated by CaMKII thereby contributing to SR Ca 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 leak and consequently increased SR Ca load. Thus, CaMKII inhibition appears to be a possible therapeutic option for patients with HF and merits further investigation.