TBC1D15 deficiency protects against doxorubicin cardiotoxicity via inhibiting DNAPKcs cytosolic retention and DNA damage  

作　　者：Wenjun Yu Haixia Xu Zhe Sun Yuxin Du Shiqun Sun Miyesaier Abudureyimu Mengjiao Zhang Jun Tao Junbo Ge Jun Ren Yingmei Zhang 

机构地区：[1]Department of Cardiology and Shanghai Institute of Cardiovascular Diseases,Zhongshan Hospital,Fudan University,Shanghai 200032,China [2]National Clinical Research Center for Interventional Medicine,Shanghai 200032,China [3]Department of Cardiovascular Surgery,Zhongnan Hospital of Wuhan University,Wuhan 430071,China [4]Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery,Wuhan 430071,China [5]Department of Cardiology,Affiliated Hospital of Nantong University,Nantong 226001,China [6]Cardiovascular Department,Shanghai Xuhui Central Hospital,Zhongshan-Xuhui Hospital,Fudan University,Shanghai 200030,China [7]Department of Cardiovascular Surgery,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou 510000,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第12期4823-4839,共17页药学学报（英文版）

基　　金：supported by the National Science Foundation of China(82130011,81770261,91749128,and 81900233);the Fundamental Research Funds for the Central Universities(2042022kf1125,China);the Outstanding Young and Middleaged Talents Training Program of Zhongnan Hospital of Wuhan University(ZNYQ2022002,China).

摘　　要：Clinical application of doxorubicin(DOX)is heavily hindered by DOX cardiotoxicity.Several theories were postulated for DOX cardiotoxicity including DNA damage and DNA damage response(DDR),although the mechanism(s)involved remains to be elucidated.This study evaluated the potential role of TBC domain family member 15(TBC1D15)in DOX cardiotoxicity.Tamoxifen-induced cardiac-specific Tbcldi5 knockout(Tbcldi5^(CKO))or Tbcldi5 knockin(Tbcldi5^(CKI))male mice were challenged with a single dose of DOx prior to cardiac assessment 1 week or 4 weeks following DOX challenge.Adenoviruses encoding TBC1D15 or containing shRNA targeting Tbcld15 were used for Tbcld15 overexpression or knockdown in isolated primary mouse cardiomyocytes.Our results re-vealed that DOX evoked upregulation of TBC1D15 with compromised myocardial function and overt mortality,the effects of which were ameliorated and accentuated by Tbcldi5 deletion and Tbcld15 overexpression,respectively.DOX overtly evoked apoptotic cell death,the effect of which was alleviated and exacerbated by Tbcld15 knockout and overexpression,respectively.Meanwhile,DOX provoked mitochondrial membrane potential collapse,oxidative stress and DNA damage,the effects of which were mitigated and exacerbated by Tbcld15 knockdown and overexpression,respectively.Further scrutiny revealed that TBC1D15 fostered cytosolic accumulation of the cardinal DDR element DNA-dependent protein kinase catalytic subunit(DNA-PKcs).Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation denoted an interaction between TBCID15 and DNA-PKcs at the segment 594-624 of TBC1D15.Moreover,overexpression of TBC1D15 mutant(A594-624,deletion of segment 594-624)failed to elicit accentuation of DOX-induced cytosolic retention of DNA-PKcs,DNA damage and cardiomyocyte apoptosis by TBC1D15 wild type.However,Tbcld15 deletion ameliorated DOXinduced cardiomyocyte contractile anomalies,apoptosis,mitochondrial anomalies,DNA damage and cytosolic DNA-PKcs accumulation,which were canceled off by DNA-PKcs inhibition

关 键 词：DOXORUBICIN CARDIOTOXICITY DNA damage DNA damage response Mitochondrial anomalies Cardiomyocyte apoptosis TBC1D15 DNA-PKCS 

分 类 号：R54[医药卫生—心血管疾病]