Abstract 14691: Inhibition of Activin A is the Novel Therapeutic Target for Heart Failure
Paracrine effects are thought to be the major mechanisms of cardiac cell therapy. We previously reported that bone marrow mononuclear cells (BMMNC) infusion improved cardiac function of non-ischemic dilated cardiomyopathy (DCM) mice via restoring the serum growth hormone (GH) levels. However, the underling mechanisms of impaired GH expression in heart failure remain unclear. Accordingly we assessed the hypothesis that inhibition of the molecule that negatively regulates GH expression might be the novel therapeutic strategy for heart failure. αMHC promoter driven epidermal growth factor receptor dominant negative (EGFRdn) mice and doxorubicin-treated mice (DOX) were used as DCM mice. Whole blood was also isolated from idiopathic DCM patients. Since activin A has been reported to downregulate GH expression by reducing the stability of pit-1, we investigated the role of activin A in the downregulation of GH in BMMNC. Serum activin A levels were significantly higher in EGFRdn, DOX mice and DCM patients than in wild-type mice and healthy subjects (n=5∼11, p<0.05). When BMMNC were cultured with activin A, mRNA and protein levels of GH were significantly downregulated. Furthermore, the GH levels in conditioned medium (CM) from PBMNC of DCM patients was lower than that in healthy subjects, suggesting that the higher activin A levels might also inhibit GH expression in heart failure patients. Next we examined whether humoral factors upregulated in heart failure might regulate activin A expression. AngII and TNFα increased the activin A levels in CM of PBMNC in a dose-dependent manner and the increased activin A levels were inhibited by the treatment with a NFκB inhibitory peptide. Finally to elucidate the role of activin A in EGFRdn mice, anti-activin A antibody was injected intraperitoneally for 2 weeks. Inhibition of activin A significantly increased serum GH levels in EGFRdn mice (n=7, p<0.05). Furthermore, FS and +dp/dt in EGFRdn mice treated with anti-activin A antibody were markedly improved compared with EGFRdn mice treated with isotype control (n=7, p<0.05). In conclusion, activin A might cause heart failure by suppressing GH activity and that inhibition of activin A might become a novel strategy for the treatment of heart failure.
- © 2011 by American Heart Association, Inc.