Abstract 12784: Caloric Restriction Ameliorates Myocardial Ischemia/reperfusion Injury by Suppressing Complement Activation in a Sirt1-dependent Manner
BACKGROUNDS: Increasing evidence demonstrates that sirt1, a NAD+-dependent protein deacetylase, mediates preferable effects of caloric restriction (CR). In addition, cardiac sirt1 is reported to play an important role in the adaptive response against various stresses such as ischemia/reperfusion (I/R), fasting, and pressure overload. However, direct evidence that cardiac sirt1 mediates cardioprotection afforded by CR was lacking. To address this issue, we investigated the effect of CR on myocardial I/R injury in cardiomyocyte-specific sirt1 knockout mice (sirt1flox/flox,α-MHC-Cre: CM-sirt1 KO) and evaluated sirt1-dependent mechanism of cardioprotection by CR.
METHODS AND RESULTS: We subjected 3-month-old CM-sirt1 KO and control mice (sirt1flox/flox: Cont) to either ad libitum (AL)-feeding or CR (-40%) for 3 months. Isolated perfused hearts were subjected to 25 min of global I, followed by 60 min of R. (1) The expression levels of sirt1 protein in CM-sirt1 KO hearts was 64% of those in Cont hearts (Fig. A). (2) The degree of myocardial I/R injury in AL CM-sirt1 KO was more severe than in AL Cont. CR-induced cardioprotection was observed in Cont, but not in CM-sirt1 KO (Figs. B and C). (3) DNA microarray analysis and subsequent validation by quantitative PCR revealed that CR significantly suppressed the expression levels of C3 (complement component 3) gene in mouse hearts in a sirt1-dependent manner (Fig. D). Thus, myocardial C3d deposition was evaluated as a marker of complement activation during I/R. Myocardial C3d deposition after I/R was significantly attenuated with CR in Cont, but not in CM-sirt1 KO.
CONCLUSIONS: These results demonstrated for the first time, that (1) cardiac sirt1 is essential for CR-induced cardioprotection, (2) CR regulates cardiac complement system in a sirt1-dependent manner, and (3) CR attenuates myocardial I/R injury by suppressing complement activation during I/R.
- © 2012 by American Heart Association, Inc.