Abstract 3465: Fkbp12.6 Overexpression in Mouse Cardiac Myocytes Offers Minor Protection Against Pressure Overload-Induced Cardiac Remodeling and Failure
Alterations in RyR2 function is a hallmark of heart failure (HF). Decreased FKBP12.6 binding to RyR2 has been put forward to explain the diastolic SR Ca2+ leakage observed in this condition. Previous work in the mouse has shown that cardiac FKBP12.6 overexpression protects against the development of myocardial infarction-induced heart failure. We tested the hypothesis that cardiac FKBP12.6 overexpression protects against transverse aortic constriction (TAC)-induced cardiac remodeling and failure. We used a mouse model of conditional cardiac-specific FKBP12.6 overexpression. Ten weeks after TAC, male transgenic mice (TG) and their wild-type controls (WT) underwent heart catheterization. Hemodynamic and gravimetric data are shown in the table⇓. Ventricular expression of the hypertrophic gene program and calcium handling proteins were assessed by real-time PCR and Western blot, respectively. Ten weeks after TAC, the mortality rate was 23% in WT and 13% in TG (14/60 vs 5/39, ns). The percentage of mice with HF, estimated on the presence of pulmonary oedema, was 42% in WT-TAC and 32% in TG-TAC (15/36 vs 7/22, ns). BNP mRNA level increased 2.8 fold in WT-TAC (p<0.01 vs WT-Shams) and 2.4 fold in TG-TAC (p<0.01 vs TG-Shams). α-skeletal actin mRNA level increased 4.3 fold in WT-TAC (p<0.001 vs WT-Shams) and 3.8 fold in TG-TAC (p<0.001 vs TG-Shams). β-MHC/α-MHC mRNA ratio increased 2.8 fold in WT-TAC (p<0.01 vs WT-Shams) and 4.3 fold in TG-TAC (p<0.05 vs TG-Shams). RyR2 protein level decreased by 58% in WT-TAC and 41% in TG-TAC (p<0.01 and p<0.05 vs sham-operated mice, respectively). SERCA2a protein level decreased by 29% in WT-TAC and 16% in TG-TAC (p<0.01 and p<0.05 vs sham-operated mice, respectively). No statistical difference was found between TG-TAC and WT-TAC for any of these parameters.
Conclusion: Cardiac FKBP 12.6 overexpression offers weak protection if any against TAC-induced cardiac remodeling and failure in the mouse.