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Abstract P186: IL-10 Mitigates Adverse Cardiac Remodeling and Improves Left Ventricle Function in Pressure Overload--Induced Hypertrophy


 Background:
 Hypertrophy associated heart failure remain the leading cause of death worldwide. Inflammatory cytokines play critical role in adverse cardiac remodeling and heart failure. Therefore, approaches geared towards inhibiting cardiac inflammation may provide therapeutic benefits. Thus, we tested the hypothesis that anti-inflammatory cytokine, IL-10, therapy might inhibit pressure overload-induced cardiac remodeling.
 
 
 Methods and Results:
 Cardiac hypertrophy was induced in Wild-type (WT) and IL-10-knockout (KO) mice by isoproterenol (ISO; 45mg/kg b.wt./day, 14 days) infusion through mini-osmotic pumps. Control groups mice received saline. ISO-induced increase in heart weight/tibia length ratio in WT was further increased in KO mice. ISO-mediated cardiac dysfunction (%EF and %FS) in WT mice were exaggerated in KO mice. KO mice displayed higher expression of fetal genes (ANP and BNP) and inflammatory cytokines (TNFα and IL-1β). ISO-treated KO mice had notably higher fibrosis and apoptosis than the WT.
 Interestingly, systemic recombinant IL-10 administration markedly attenuated effects of ISO and improved left ventricle function, reversed fetal gene expression, fibrosis and apoptosis both in WT and in KO mice.
 To further understand the mechanism of IL-10 protection, NRCM and H9C2 cells were treated with ISO (10µM) and/or IL-10 (20ng/mL),
 in vitro
 . ISO significantly increased the mRNA expression of ANP and BNP as well as of inflammatory cytokines which was markedly reduced by IL-10. ISO treatment also induced the activation of p38, ERK1/2 MAP kinases and of NFkB while it inhibited STAT-3 phosphorylation. Interestingly, co-treatment with IL-10 suppressed p38 and ERK1/2 phosphorylation while enhancing STAT-3 phosphorylation. Interestingly, ISO-induced nuclear translocation of NFkB was mimicked by STAT3 specific inhibitor cucurbitacin, suggesting STAT3 as the downstream target of IL-10 effects.
 
 
 Conclusion:
 Our studies suggest that IL-10 treatment not only inhibits the progression but also reverses the pressure overload-induced adverse cardiac remodeling. Ongoing investigations will further provide a better understanding on the mechanistic and therapeutic aspects of IL-10 on hypertrophic remodeling and heart failure.
