Physiological and pathological Roles of the CD38/cyclic ADP-ribose signal system in cardiac myocytes

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CD38 catalyzes both the formation and hydrolysis of cyclic ADP-ribose (cADPR). To elucidate whether the CD38/cADPR signaling system plays a significant role in Ca^<2+> cycling in vivo, we analyzed the myocardium of CD38 knockout mice (CD38KO).In CD38KO, the myocardial cADPR content was reduced by 85% compared with wild-type mice (WT), and cardiac hypertrophy developed only in males but not in females. At physiological temperature (36.1±0.2℃), none of the parameters for Ca^<2+> transients and forces of papillary muscles differed between WT and CD38KO. In contrast, at lower temperature (26.8±0.2℃), at which the effects of cADPR are supposed to be lost, the peak [Ca^<2+>]I was significantly increased and the time constant of decline in [Ca^<2+>]I and minimum of the first derivative of force were significantly decreased in both-gender CD38KO compared with gender-matched WT. Additionally, in female CD38KO, the maximum of the first derivative of force was significantly increased. Western blot analysis revealed that, in both-gender CD38KO, the expression levels of sarcoplasmic reticulum Ca^<2+> ATPase type 2 (SERCA2) and the SERCA2-to-phospholamban ratio were significantly increased compared with WT. The ryanodine receptor protein level was significantly increased in female CD38KO, but not in male CD38KO, compared with gender-matched WT.These data suggest the CD38/cADPR signaling system plays an important role in intracellular Ca2+ homeostasis in cardiac myocytes in vivo. Its deficiency was compensated differentially according to gender, which might be responsible at least partially for the different hypertrophic responses between genders.