Limitations of FKBP12.6-directed treatment strategies for maladaptive cardiac remodeling and heart failure

Limitations of FKBP12.6-directed treatment strategies for maladaptive cardiac remodeling and heart failure

Abstract Sarcoplasmic reticulum (SR) calcium (Ca) leak can be reduced by enhancing FKBP12.6 binding to SR Ca release channels (RyR2) and expression of a “sticky” FKBP12.6D37S mutant may correct reduced binding stoichiometry in RyR2 from failing hearts. Both calcium/calmodulin-dependent protein kinas...

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Bibliographic Details
Published in:Journal of molecular and cellular cardiology Vol. 50; no. 1; pp. 33 - 42
Main Authors: Seidler, Tim, Teucher, Nils, Hellenkamp, Kristian, Unsöld, Bernhard, Grebe, Cornelia, Kramps, Petra, Schotola, Hanna, Wagner, Stefan, Schöndube, Friedrich A, Hasenfuss, Gerd, Maier, Lars S
Format: Journal Article
Language:English
Published: England Elsevier Ltd 01-01-2011
Subjects:
Animals
Ca sparks
Ca transients
Calcium - metabolism
Calcium Signaling - genetics
Calcium Signaling - physiology
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism
CaMK
Cardiovascular
FKBP
Heart failure
Heart Failure - genetics
Heart Failure - metabolism
Maladaptive remodelling
Mice
Mice, Mutant Strains
Mice, Transgenic
Microscopy, Confocal
Pressure overload
Ryanodine Receptor Calcium Release Channel - metabolism
Tacrolimus Binding Proteins - genetics
Tacrolimus Binding Proteins - metabolism
Transgenic mice
Ventricular Remodeling - genetics
Ventricular Remodeling - physiology
Heart failure
FKBP
CaMK
Transgenic mice
Maladaptive remodelling
Pressure overload
Ca transients
Ca sparks
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Summary:Abstract Sarcoplasmic reticulum (SR) calcium (Ca) leak can be reduced by enhancing FKBP12.6 binding to SR Ca release channels (RyR2) and expression of a “sticky” FKBP12.6D37S mutant may correct reduced binding stoichiometry in RyR2 from failing hearts. Both calcium/calmodulin-dependent protein kinase IIδc (CaMKIIδc) and protein kinase A (PKA) are activated in heart failure and promote SR Ca leak at RyR2. It is possible that FKBP12.6 dissociation from RyR2 may promote remodeling and that interventions to reassociate FKBP12.6 with RyR2 reflect a future therapeutic strategy. We created transgenic (TG) mice expressing FKBP12.6D37S and tested their capacity to improve intracellular Ca handling and pathological remodeling in vivo. FKBP12.6D37S TG mice were cross-bred with CaMKIIδc TG mice, which are known to exhibit pronounced RyR2 dysfunction and heart failure. We observed a significant improvement of post-rest Ca transients and a higher SR Ca content in FKBP12.6D37S TG mice. In double-TG mice, a marked reduction of SR Ca spark frequency indicated reduced SR Ca leak but neither SR Ca transient amplitude, SR Ca content nor morphological or functional parameters improved in vivo . Likewise, FKBP12.6D37S TG mice subjected to increased afterload after aortic banding exhibited higher SR Ca load but did not exhibit any improvement in hypertrophic growth or functional decline. Enhancement of FKBP12.6-RyR2 binding markedly reduced RyR2 Ca leak in CaMKIIδc-induced heart failure and in pressure overload. Our data suggest that activation of CaMKIIδc and pressure overload confer significant resistance towards approaches aiming at FKBP12.6-RyR2 reconstitution in heart failure and maladaptive remodeling, although RyR2 Ca leak can be reduced.
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ISSN:0022-2828
1095-8584
DOI:10.1016/j.yjmcc.2010.08.016