SR-targeted CaMKII inhibition improves SR Ca2+ handling, but accelerates cardiac remodeling in mice overexpressing CaMKIIδC

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Cardiac myocyte overexpression of CaMKIIδC leads to cardiac hypertrophy and heart failure (HF) possibly caused by altered myocyte Ca2+ handling. A central defect might be the marked CaMKII-induced increase in diastolic sarcoplasmic reticulum (SR) Ca2+ leak which decreases SR Ca2+ load and Ca2+ transient amplitude. We hypothesized that inhibition of CaMKII near the SR membrane would decrease the leak, improve Ca2+ handling and prevent the development of contractile dysfunction and HF. To test this hypothesis we crossbred CaMKIIδC 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 Ca2+ leak, assessed both as diastolic Ca2+ shift into SR upon tetracaine in intact myocytes or integrated Ca2+ spark release in permeabilized myocytes, was significantly reduced. The reduced leak was accompanied by enhanced SR Ca2+ load and twitch amplitude in double-transgenic mice (vs. CaMK), without changes in SERCA expression or NCX function. However, despite the improved myocyte Ca2+ 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 Ca2+ handling, it does not necessarily rescue the HF phenotype. This implies that a non-SR CaMKIIδC exerts SR-independent effects that contribute to hypertrophy and HF, and this CaMKII pathway may be exacerbated by the global enhancement of Ca transients.