Abstract 152: IL-10 Inhibits Angiotensin II-induced Pathological Autophagy in Myocardium.

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Background: In heart, persistent pressure overload causes pathological autophagy leading to cardiac cell death and heart failure. The role IL-10, a pleiotropic anti-inflammatory cytokine, on pathological autophagy is largely unknown. Here we hypothesized that IL-10 inhibits stress-induced pathological autophagy and therefore attenuates cardiac cells death and improve heart function.

Method and Results: Cardiac stress was induced in C57 BL/6 mice by Angiotensin II treatment (Ang II-1.2mg.kg b.wt/day for 28 days) using mini osmotic pumps. Ang II treatment markedly induced autophagy in mice as measured by electron microscopy (autophagosome numbers) and Western blotting (Becline1 and LC3II proteins expression). Interestingly, systemic recombinant mouse IL-10 administration markedly inhibited Ang II-induced autophagy. To further understand the mechanism of IL-10 protection, neonatal rat ventricular myocytes (NRCM) were transfected with monomeric Red Fluorescent Protein-Enhanced Green Fluorescent Protein (mRFP-EGFP) tandem fluorescent-tagged LC3 (tfLC3) adenovirus (to measure autophagic flux) and then treated with AngII (1μM) and/or IL-10 (20ng/mL), in vitro. Ang II treatment significantly increased the numbers of both yellow (merged EGFP and mRFP signals) and red puncta, indicating active formation of both autophagosomes and autolysosomes, however, this flux was strongly inhibited by IL-10. Furthermore, Ang II significantly increased the Beclin1 and LC3II proteins expression, which was markedly reduced by IL-10 as measured by Western blot analysis. In addition, Ang II-inhibited AKT signaling (anti-autophagic signaling component) was strongly enhanced by IL-10. Ang II-induced autophagic signaling was mimicked by AKT inhibitor, suggesting AKT as the downstream target of IL-10 effects.

Conclusion: Inhibition of pathological autophagy is a novel mechanism for cardio-protective effects of IL-10.

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