title: CaMKII inhibition in heart failure, beneficial, harmful, or both.
abstract: Calmodulin-dependent protein kinase II (CaMKII) has been proposed to be a therapeutic target for heart failure (HF). However, the cardiac effect of chronic CaMKII inhibition in HF has not been well understood. We have tested alterations of Ca(2+) handling, excitation-contraction coupling, and in vivo β-adrenergic regulation in pressure-overload HF mice with CaMKIIδ knockout (KO). HF was produced in wild-type (WT) and KO mice 1 wk after severe thoracic aortic banding (sTAB) with a continuous left ventricle (LV) dilation and reduction of ejection fraction for up to 3 wk postbanding. Cardiac hypertrophy was similar between WT HF and KO HF mice. However, KO HF mice manifested exacerbation of diastolic function and reduction in cardiac reserve to β-adrenergic stimulation. Compared with WT HF, L-type calcium channel current (I(Ca)) density in KO HF LV was decreased without changes in I(Ca) activation and inactivation kinetics, whereas I(Ca) recovery from inactivation was accelerated and Ca(2+)-dependent I(Ca) facilitation, a positive staircase blunted in WT HF, was recovered. However, I(Ca) response to isoproterenol was reduced. KO HF myocytes manifested dramatic decrease in sarcoplasmic reticulum (SR) Ca(2+) leak and slowed cytostolic Ca(2+) concentration decline. Sarcomere shortening was increased, but relaxation was slowed. In addition, an increase in myofilament sensitivity to Ca(2+) and the slow skeletal muscle troponin I-to-cardiac troponin I ratio and interstitial fibrosis and a decrease in Na/Ca exchange function and myocyte apoptosis were observed in KO HF LV. CaMKIIδ KO cannot suppress severe pressure-overload-induced HF. Although cellular contractility is improved, it reduces in vivo cardiac reserve to β-adrenergic regulation and deteriorates diastolic function. Our findings challenge the strategy of CaMKII inhibition in HF.
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Cheng
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Dongwu
authors.initials: D
authors.lastname: Lai
authors.forename: Arnaud
authors.initials: A
authors.lastname: Guilbert
authors.forename: Hyun Joung
authors.initials: HJ
authors.lastname: Lim
authors.forename: Thitima
authors.initials: T
authors.lastname: Keskanokwong
authors.forename: Yanggan
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy*; D006352:Heart Ventricles / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009210:Myofibrils / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use* / Q000633:toxicity; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology; D012518:Sarcomeres / Q000187:drug effects; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism; D014463:Ultrasonography
chemical_list: D000318:Adrenergic beta-Agonists; D015220:Calcium Channels; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011943:Receptors, Adrenergic, beta; D019831:Sodium-Calcium Exchanger; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases