Interleukin-10 inhibits chronic angiotensin II-induced pathological autophagy.
Interleukin-10 inhibits chronic angiotensin II-induced pathological autophagy.
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DOI：
10.1016/j.yjmcc.2015.11.004
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发表时间：
2015-12
影响因子：
5
通讯作者：
Verma SK
中科院分区：
文献类型：
--
作者：
Kishore R;Krishnamurthy P;Garikipati VN;Benedict C;Nickoloff E;Khan M;Johnson J;Gumpert AM;Koch WJ;Verma SK
虽然自噬是维持细胞稳态的重要细胞挽救过程，但病理性自噬可导致心脏异常并最终导致心力衰竭。因此，严格调控自噬过程对于治疗慢性心力衰竭具有重要意义。以前，我们已经表明，IL-10强烈抑制压力超负荷诱导的肥大和心力衰竭，但IL-10在调节病理性自噬中的作用是未知的。在这里，我们测试的假设，IL-10抑制血管紧张素II诱导的病理性自噬，这一过程，在一定程度上，导致改善心脏功能。慢性Ang II强烈诱导IL-10敲除小鼠的死亡率和心功能障碍。IL-10的缺失加重了病理性自噬对Ang II治疗的反应。在分离的心肌细胞中，IL-10减弱Ang II诱导的病理性自噬并激活Akt/mTORC 1信号传导。药理学或分子抑制Akt和mTORC 1信号减弱IL-10对Ang II诱导的病理性自噬的作用。此外，自噬通量实验中的溶酶体抑制进一步证实了IL-10通过mTORC 1信号传导抑制病理性自噬。我们的数据表明IL-10在调节病理性自噬中的新作用;因此可以作为治疗慢性心脏病的潜在治疗分子。
Although autophagy is an essential cellular salvage process to maintain cellular homeostasis, pathological autophagy can lead to cardiac abnormalities and ultimately heart failure. Therefore, a tight regulation of autophagic process would be important to treat chronic heart failure. Previously, we have shown that IL-10 strongly inhibited pressure overload-induced hypertrophy and heart failure, but role of IL-10 in regulation of pathological autophagy is unknown. Here we tested the hypothesis that IL-10 inhibits angiotensin II-induced pathological autophagy and this process, in part, leads to improve cardiac function. Chronic Ang II strongly induced mortality, cardiac dysfunction in IL-10 Knockout mice. IL-10 deletion exaggerated pathological autophagy in response to Ang II treatment. In isolated cardiac myocytes, IL-10 attenuated Ang II-induced pathological autophagy and activated Akt/mTORC1 signaling. Pharmacological or molecular inhibition of Akt and mTORC1 signaling attenuated IL-10 effects on Ang II-induced pathological autophagy. Furthermore, lysosomal inhibition in autophagic flux experiments further confirmed that IL-10 inhibits pathological autophagy via mTORC1 signaling. Our data demonstrate a novel role of IL-10 in regulation of pathological autophagy; thus can act as a potential therapeutic molecule for treatment of chronic heart disease.