Abstract 13686: IL10 Attenuates Cardiac Remodeling and Improves Left Ventricular Function in Pressure Overload-Induced Hypertrophy by Inhibiting Inflammation Via Stat3-Mediated Inhibition of NFkB
Background: Inflammatory cytokines play a critical role in adverse hypertrophic cardiac remodeling and heart failure. Therefore, approaches geared towards inhibiting cardiac inflammation may provide therapeutic benefits. Thus, we tested the hypothesis that genetic deletion of interleukin-10 (IL10), a potent anti-inflammatory cytokine, may exacerbate pressure-overload induced adverse cardiac remodeling and hypertrophy and that IL10 therapy might inhibit this pathology.
Methods and Results: Cardiac hypertrophy was induced in Wild-type (WT) and IL10-knockout (KO) mice by isoproterenol (ISO; 45mg/kg b.wt./day, 14 days) infusion through mini-osmotic pumps. Control groups 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. ISO-treated KO mice displayed higher expression of fetal and inflammatory genes than WT. ISO-treated KO mice had notably higher fibrosis and apoptosis than the WT. Interestingly, systemic recombinant mouse IL10 therapy 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 IL10 protection, neonatal rat ventricular myocytes (NRCM) were treated with ISO (10µM) and/or IL10 (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 IL10. At the signaling level, ISO treatment induced the activation of NFkB while it inhibited STAT3 phosphorylation. Interestingly, co-treatment with IL10 suppressed ISO effects on NFkB and STAT3. Moreover, inhibition of IL10 induced STAT3 activation by specific inhibitor curcurbitacin I reversed the beneficial effects of IL10 suggesting STAT3 as the downstream target of IL10 effects.
Conclusion: Our studies suggest that IL10 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 IL10 on hypertrophic remodeling and heart failure.
- © 2011 by American Heart Association, Inc.