國家衛生研究院 NHRI:Item 3990099045/13005
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    题名: TLR9 binding to beclin 1 and mitochondrial SIRT3 by a sodium‐glucose co‐transporter 2 inhibitor protects the heart from doxorubicin toxicity
    作者: Wang, CY;Chen, CC;Lin, MH;Su, HT;Ho, MY;Yeh, JK;Tsai, ML;Hsieh, IC;Wen, MS
    贡献者: Institute of Cellular and Systems Medicine
    摘要: Large cardiovascular outcome trials have reported favorable effects of sodium‐glucose co-transporter 2 (SGLT2) inhibitors on heart failure. To study the potential mechanism of the SGLT2 inhibition in heart failure, we used the murine doxorubicin‐induced cardiomyopathy model and identified the toll‐like receptor 9 (TLR9), NAD‐dependent deacetylase sirtuin‐3 (SIRT3), and Beclin 1, acting in a complex together in response to empagliflozin treatment. The interactions and implications in mitochondrial function were evaluated with TLR9 deficient, SIRT3 deficient, Beclin 1 haplodeficient, and autophagy reporter mice and confirmed in a patient with SIRT3 point mutation and reduced enzymatic activity. The SGLT2 inhibitor, empagliflozin, protects the heart from doxorubicin cardiomyopathy in mice, by acting through a novel Beclin 1‐toll‐like receptor (TLR) 9‐sirtuin‐(SIRT) 3 axis. TLR9 and SIRT3 were both essential for the protective effects of empagliflozin. The dilated cardiomyopathy patient with SIRT3 point mutation and reduced enzymatic activity is associated with reduced TLR9 activation and the absence of mitochondrial responses in the heart after the SGLT2 inhibitor treatment. Our data indicate a dynamic communication between autophagy and Beclin 1‐TLR9‐SIRT3 complexes in the mitochondria in response to empagliflozin that may serve as a potential treatment strategy for heart failure.
    日期: 2020-10-29
    關聯: Biology. 2020 Oct 29;9(11):Article number 369.
    Link to: http://dx.doi.org/10.3390/biology9110369
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2079-7737&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000592911200001
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85094558644
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