Abstract
Preventing Ca(2+)-leak during diastole may provide a means to improve overall cardiac function. The immunosuppressant FK506-binding protein 12.6 (FKBP12.6) regulates ryanodine receptor-2 (RyR2) gating and binds to and inhibits calcineurin (Cn). It is also involved in the pathophysiology of heart failure (HF). Here, we investigated the effects of FKBP12.6 over-expression and gender on Ca(2+)-handling proteins (RyR2, SERCA2a/PLB, and NCX), and on pro-(CaMKII, Cn/NFAT) and anti-hypertrophic (GSK3β) signalling pathways in a thoracic aortic constriction (TAC) mouse model. Wild type mice (WT) and mice over-expressing FKBP12.6 of both genders underwent TAC or sham-operation (Sham). FKBP12.6 over-expression ameliorated post-TAC survival rates in both genders. Over time, FKBP12.6 over-expression reduced the molecular signature of left ventricular hypertrophy (LVH) and the transition to HF (BNP and β-MHC mRNAs) and attenuated Cn/NFAT activation in TAC-males only. The gender difference in pro- and anti-hypertrophic LVH signals was time-dependent: TAC-females exhibited earlier pathological LVH associated with concomitant SERCA2a down-regulation, CaMKII activation, and GSK3β inactivation. Both genotypes showed systolic dysfunction, possibly related to down-regulated RyR2, but only FK-TAC-males exhibited preserved diastolic LV function. Although FKBP12.6 over-expression did not impact the vicious cycle of TAC-induced HF, this study reveals some subtle sequential and temporal gender differences in Ca(2+)-signalling pathways of pathological LVH.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aorta, Thoracic / pathology
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Calcineurin Inhibitors
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Calcium / physiology
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Calcium Signaling / genetics*
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Calcium Signaling / physiology
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / physiology
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Disease Models, Animal
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Down-Regulation
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Female
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Gene Expression Profiling*
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Glycogen Synthase Kinase 3
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Glycogen Synthase Kinase 3 beta
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Heart / anatomy & histology
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Heart / physiopathology
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Heart Failure / genetics
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Heart Failure / metabolism
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Heart Failure / surgery
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Homeodomain Proteins / antagonists & inhibitors
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Humans
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Hypertrophy, Left Ventricular / genetics
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Hypertrophy, Left Ventricular / metabolism
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Hypertrophy, Left Ventricular / physiopathology*
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Major Histocompatibility Complex
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Male
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Mice
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Mice, Transgenic
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Natriuretic Peptide, Brain / analysis
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Natriuretic Peptide, Brain / metabolism
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Phenotype
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Random Allocation
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Ryanodine Receptor Calcium Release Channel / physiology*
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Sarcoplasmic Reticulum Calcium-Transporting ATPases / antagonists & inhibitors
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Sex Factors
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Signal Transduction / physiology
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Tacrolimus Binding Proteins / physiology*
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Ventricular Pressure / physiology*
Substances
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Calcineurin Inhibitors
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FKBP12.6 protein, mouse
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Homeodomain Proteins
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Ryanodine Receptor Calcium Release Channel
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Tlx2 protein, mouse
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Natriuretic Peptide, Brain
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases
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Glycogen Synthase Kinase 3
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Sarcoplasmic Reticulum Calcium-Transporting ATPases
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Tacrolimus Binding Proteins
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Atp2a2 protein, mouse
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Calcium