SR-targeted CaMKII inhibition improves SR Ca²+ handling, but accelerates cardiac remodeling in mice overexpressing CaMKIIδC.
Cardiac myocyte overexpression of CaMKIIδ(C) leads to cardiac hypertrophy and heart failure (HF) possibly caused by altered myocyte Ca(2+) handling. A central defect might be the marked CaMKII-induced increase in diastolic sarcoplasmic reticulum (SR) Ca(2+) leak which decreases SR Ca(2+) load and Ca(2+) transient amplitude. We hypothesized that inhibition of CaMKII near the SR membrane would decrease the leak, improve Ca(2+) handling and prevent the development of contractile dysfunction and HF. To test this hypothesis we crossbred CaMKIIδ(C) overexpressing mice (CaMK) with mice expressing the CaMKII-inhibitor AIP targeted to the SR via a modified phospholamban (PLB)-transmembrane-domain (SR-AIP). There was a selective decrease in the amount of activated CaMKII in the microsomal (SR/membrane) fraction prepared from these double-transgenic mice (CaMK/SR-AIP) mice. In ventricular cardiomyocytes from CaMK/SR-AIP mice, SR Ca(2+) leak, assessed both as diastolic Ca(2+) shift into SR upon tetracaine in intact myocytes or integrated Ca(2+) spark release in permeabilized myocytes, was significantly reduced. The reduced leak was accompanied by enhanced SR Ca(2+) load and twitch amplitude in double-transgenic mice (vs. CaMK), without changes in SERCA expression or NCX function. However, despite the improved myocyte Ca(2+) handling, cardiac hypertrophy and remodeling was accelerated in CaMK/SR-AIP and cardiac function worsened. We conclude that while inhibition of SR localized CaMKII in CaMK mice improves Ca(2+) handling, it does not necessarily rescue the HF phenotype. This implies that a non-SR CaMKIIδ(C) exerts SR-independent effects that contribute to hypertrophy and HF, and this CaMKII pathway may be exacerbated by the global enhancement of Ca transients.
Huke
Sabine
S
Vanderbilt University, Nashville, TN 37232, USA. sabine.huke@vanderbilt.edu
Desantiago
Jaime
J
Kaetzel
Marcia A
MA
Mishra
Shikha
S
Brown
Joan H
JH
Dedman
John R
JR
Bers
Donald M
DM
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D004452:Echocardiography; D006352:Heart Ventricles / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium