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

• Published in: Canadian journal of physiology and pharmacology 2011-11, Vol.89 (11), p.769-782
• Main Authors: Previlon, Miresta, Pezet, Mylene, Semprez, Fannie, Mercadier, Jean-Jacques, Rouet-Benzineb, Patricia
• Format: Article
• Language: English
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/y11-075

Preventing Ca super(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 super(2+)-handling proteins (RyR2, SERCA2a/PLB, and NCX), and on pro-(CaMKII, Cn/NFAT) and anti-hypertrophic (GSK3 beta ) 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 beta -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 GSK3 beta 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 super(2+)-signalling pathways of pathological LVH.Original Abstract: Prevenir la fuite du Ca super(2+) au cours de la diastole pourrait s'averer une strategie d'amelioration de la fonction cardiaque globale. La proteine FKBP12,6 controle l'ouverture des recepteurs 2 de la ryanodine (RyR2) et inhibe la calcineurine (Cn). Elle est aussi impliquee dans la pathophysiologie de l'insuffisance cardiaque (HF). Dans cette etude, on analyse les effets de la surexpression de FKBP12,6 et du genre sur les proteines de l'homeostasie calcique (RyR2, SERCA2a/PLB et NCX) et sur les voies de signalisation pro-(CaMKII, Cn/NFAT) et anti-hypertrophiques (GSK3 beta ) dans un modele (souris) d'hypertrophie cardiaque induite par la constriction de l'aorte thoracique (TAC). On soumet les souris surexprimant la FKBP12,6 et des souris de type sauvage (WT) des deux sexes a une operation TAC ou a une operation simulee (Sham). La surexpression de FKBP12,6 ameliore le taux de surv