Related Experiment Video
Updated: May 28, 2026
Transverse Aortic Constriction in Mice
Published on: April 21, 2010
FKBP12.6 mice display temporal gender differences in cardiac Ca(2+)-signalling phenotype upon chronic pressure
Miresta Prévilon1, Mylène Pezet, Fannie Semprez
1Institut national de la santé et de la recherche médicale (Inserm), UMR U698, Paris, France.
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.
Insights
Overexpressing FKBP12.6 improves survival and reduces cardiac hypertrophy in mice after thoracic aortic constriction. This study highlights subtle, time-dependent gender differences in calcium signaling pathways during heart failure development.
Area of Science:
- Cardiology
- Molecular Biology
- Physiology
Background:
- Calcium (Ca2+) leak during diastole impairs cardiac function.
- FK506-binding protein 12.6 (FKBP12.6) influences ryanodine receptor-2 (RyR2) and calcineurin (Cn) activity, and is implicated in heart failure (HF).
Purpose of the Study:
- To investigate the impact of FKBP12.6 overexpression and gender on cardiac Ca2+-handling proteins and signaling pathways in a mouse model of thoracic aortic constriction (TAC).
Main Methods:
- Wild type (WT) and FKBP12.6-overexpressing (FK) mice of both genders underwent TAC or sham surgery.
- Evaluated Ca2+-handling proteins (RyR2, SERCA2a/PLB, NCX) and signaling pathways (CaMKII, Cn/NFAT, GSK3β).
- Assessed survival rates, left ventricular hypertrophy (LVH) markers (BNP, β-MHC), and cardiac function.
Main Results:
- FKBP12.6 overexpression improved post-TAC survival in both genders.
- FKBP12.6 reduced LVH and HF markers, notably attenuating Cn/NFAT activation in TAC-males.
- TAC-females showed earlier LVH with SERCA2a downregulation and CaMKII activation; FK-TAC-males preserved diastolic function.
Conclusions:
- FKBP12.6 overexpression offers partial protection against TAC-induced cardiac remodeling and dysfunction.
- Subtle, time-dependent gender differences exist in Ca2+-signaling pathways during pathological LVH.
- Further research is needed to fully elucidate FKBP12.6's role in HF pathophysiology and potential therapeutic applications.
