FKBP12.6 mice display temporal gender differences in cardiac Ca(2+)-signalling phenotype upon chronic pressure overload.
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.
Institut national de la santé et de la recherche médicale (Inserm), UMR U698, Paris, France.
Miresta
M
Prévilon
Mylène
M
Pezet
Fannie
F
Semprez
Jean-Jacques
JJ
Mercadier
Patricia
P
Rouet-Benzineb
D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000502:physiology; D020013:Calcium Signaling / Q000235:genetics* / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000033:anatomy & histology / Q000503:physiopathology; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020097:Natriuretic Peptide, Brain / Q000032:analysis / Q000378:metabolism; D010641:Phenotype; D011897:Random Allocation; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology; D022021:Tacrolimus Binding Proteins / Q000502:physiology*; D017725:Ventricular Pressure / Q000502:physiology*
D065095:Calcineurin Inhibitors; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D018398:Homeodomain Proteins; D020097:Natriuretic Peptide, Brain; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D022021:Tacrolimus Binding Proteins; C509259:FKBP1B protein, mouse; C107836:Tlx2 protein, mouse; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse; C506947:Atp2a2 protein, mouse