FKBP12.6 mice display temporal gender differences in cardiac Ca(2+)-signalling phenotype upon chronic pressure overload

Can J Physiol Pharmacol. 2011 Nov;89(11):769-82. doi: 10.1139/y11-075. Epub 2011 Oct 18.


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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta, Thoracic / pathology
  • Calcineurin Inhibitors
  • Calcium / physiology
  • Calcium Signaling / genetics*
  • Calcium Signaling / physiology
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology
  • Disease Models, Animal
  • Down-Regulation
  • Female
  • Gene Expression Profiling*
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinase 3 beta
  • Heart / anatomy & histology
  • Heart / physiopathology
  • Heart Failure / genetics
  • Heart Failure / metabolism
  • Heart Failure / surgery
  • Homeodomain Proteins / antagonists & inhibitors
  • Humans
  • Hypertrophy, Left Ventricular / genetics
  • Hypertrophy, Left Ventricular / metabolism
  • Hypertrophy, Left Ventricular / physiopathology*
  • Major Histocompatibility Complex
  • Male
  • Mice
  • Mice, Transgenic
  • Natriuretic Peptide, Brain / analysis
  • Natriuretic Peptide, Brain / metabolism
  • Phenotype
  • Random Allocation
  • Ryanodine Receptor Calcium Release Channel / physiology*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / antagonists & inhibitors
  • Sex Factors
  • Signal Transduction / physiology
  • Tacrolimus Binding Proteins / physiology*
  • Ventricular Pressure / physiology*


  • Calcineurin Inhibitors
  • FKBP12.6 protein, mouse
  • Homeodomain Proteins
  • Ryanodine Receptor Calcium Release Channel
  • Tlx2 protein, mouse
  • Natriuretic Peptide, Brain
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Tacrolimus Binding Proteins
  • Atp2a2 protein, mouse
  • Calcium