A novel therapeutic peptide targeting myocardial reperfusion injury

被引:14
作者
Boisguerin, Prisca [1 ,2 ]
Covinhes, Aurelie [3 ,4 ]
Gallot, Laura [3 ,4 ]
Barrere, Christian [3 ,4 ]
Vincent, Anne [3 ,4 ]
Busson, Muriel [5 ]
Piot, Christophe [3 ,4 ,6 ]
Nargeot, Joel [3 ,4 ]
Lebleu, Bernard [2 ]
Barrere-Lemaire, Stephanie [3 ,4 ]
机构
[1] Univ Montpellier, CNRS, CRBM, F-34293 Montpellier, France
[2] Univ Montpellier, CNRS, DIMNP, F-34095 Montpellier, France
[3] Univ Montpellier, INSERM, CNRS, IGF, F-34094 Montpellier, France
[4] Lab Excellence Ion Channel Sci & Therapeut, F-06560 Valbonne, France
[5] Univ Montpellier, INSERM, IRCM, F-34298 Montpellier, France
[6] Clin Millenaire, Dept Cardiol Intervent, F-34000 Montpellier, France
关键词
Cardioprotection; Apoptosis; Reperfusion Injury; Therapeutic peptide; DAXX; SIGNAL-TRANSDUCTION PATHWAY; CELL-DEATH; ISCHEMIA/REPERFUSION INJURY; HYDROGEN-PEROXIDE; DAXX TRAFFICKING; INFARCT SIZE; RAT HEARTS; PROTEIN; APOPTOSIS; STRESS;
D O I
10.1093/cvr/cvz145
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Aims Regulated cell death is a main contributor of myocardial ischaemia-reperfusion (IR) injury during acute myocardial infarction. In this context, targeting apoptosis could be a potent therapeutical strategy. In a previous study, we showed that DAXX (death-associated protein) was essential for transducing the FAS-dependent apoptotic signal during IR injury. The present study aims at evaluating the cardioprotective effects of a synthetic peptide inhibiting FAS:DAXX interaction. Methods and results An interfering peptide was engineered and then coupled to the Tat cell penetrating peptide (Tat-DAXXp). Its internalization and anti-apoptotic properties were demonstrated in primary cardiomyocytes. Importantly, an intravenous bolus injection of Tat-DAXXp (1mg/kg) 5min before reperfusion in a murine myocardial IR model decreased infarct size by 48% after 24h of reperfusion. In addition, Tat-DAXXp was still efficient after a 30-min delayed administration, and was completely degraded and eliminated within 24h thereby reducing risks of potential side effects. Importantly, Tat-DAXXp reduced mouse early post-infarction mortality by 67%. Mechanistically, cardioprotection was supported by both anti-apoptotic and pro-survival effects, and an improvement of myocardial functional recovery as evidenced in ex vivo experiments. Conclusions Our study demonstrates that a single dose of Tat-DAXXp injected intravenously at the onset of reperfusion leads to a strong cardioprotection in vivo by inhibiting IR injury validating Tat-DAXXp as a promising candidate for therapeutic application.
引用
收藏
页码:633 / 644
页数:12
相关论文
共 50 条
  • [1] Therapeutic Potential of a Novel Necrosis Inhibitor, 7-Amino-Indole, in Myocardial Ischemia-Reperfusion Injury
    Hwang, In-Chang
    Kim, Ju-Young
    Kim, Ji-Hyun
    Lee, Joo-Eun
    Seo, Ji-Yun
    Lee, Jae-Won
    Park, Jonghanne
    Yang, Han-Mo
    Kim, Soon-Ha
    Cho, Hyun-Jai
    Kim, Hyo-Soo
    HYPERTENSION, 2018, 71 (06) : 1143 - 1155
  • [2] CTRPs, A Novel Therapeutic Target Against Myocardial Ischemia/Reperfusion Injury
    Yuan, Yuexing
    Gao, Erhe
    Wang, Yajing
    Wang, Xiaoliang
    Yi, Wei
    Lau, Wayne Bond
    Wong, William G.
    Koch, Walter J.
    Ma, Xin
    CIRCULATION, 2010, 122 (21)
  • [3] Efficacy of a Novel Mitochondrial-Derived Peptide in a Porcine Model of Myocardial Ischemia/Reperfusion Injury
    Sharp, Thomas E., III
    Gong, Zhenwei
    Scarborough, Amy
    Goetzman, Eric S.
    Ali, Murtuza J.
    Spaletra, Pablo
    Lefer, David J.
    Muzumdar, Radhika H.
    Goodchild, Traci T.
    JACC-BASIC TO TRANSLATIONAL SCIENCE, 2020, 5 (07): : 699 - 714
  • [4] Flavonoids in myocardial ischemia-reperfusion injury: Therapeutic effects and mechanisms
    Jia, Jun-ying
    Zang, Er-huan
    Lv, Li-juan
    Li, Qin-yu
    Zhang, Chun-hua
    Xia, Ying
    Zhang, Lei
    Dang, Lian-sheng
    Li, Min-hui
    CHINESE HERBAL MEDICINES, 2021, 13 (01) : 49 - 63
  • [5] Targeting autophagy in cardiac ischemia/reperfusion injury: A novel therapeutic strategy
    Aghaei, Mehrdad
    Motallebnezhad, Morteza
    Ghorghanlu, Sajjad
    Jabbari, Ali
    Enayati, Ayesheh
    Rajaei, Maryam
    Pourabouk, Mona
    Moradi, Alireza
    Alizadeh, Ali Mohammad
    Khori, Vahid
    JOURNAL OF CELLULAR PHYSIOLOGY, 2019, 234 (10) : 16768 - 16778
  • [6] Ferroptosis: A Novel Therapeutic Target for Ischemia-Reperfusion Injury
    Chen, Yunqing
    Fan, Hongyan
    Wang, Shijun
    Tang, Guanmin
    Zhai, Changlin
    Shen, Liang
    FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 2021, 9
  • [7] DJ-1 as a Novel Therapeutic Target for Mitigating Myocardial Ischemia-Reperfusion Injury
    Zhou, Jia-Bin
    Wei, Tian-Peng
    Wu, Dan
    Zhou, Feng
    Wang, Ru-Xing
    CARDIOVASCULAR THERAPEUTICS, 2024, 2024 (01) : 6615720
  • [8] PPARβ/δ priming enhances the anti-apoptotic and therapeutic properties of mesenchymal stromal cells in myocardial ischemia-reperfusion injury
    Sarre, Charlotte
    Contreras-Lopez, Rafael
    Nernpermpisooth, Nitirut
    Barrere, Christian
    Bahraoui, Sarah
    Terraza, Claudia
    Tejedor, Gautier
    Vincent, Anne
    Luz-Crawford, Patricia
    Kongpol, Kantapich
    Kumphune, Sarawut
    Piot, Christophe
    Nargeot, Joel
    Jorgensen, Christian
    Djouad, Farida
    Barrere-Lemaire, Stephanie
    STEM CELL RESEARCH & THERAPY, 2022, 13 (01)
  • [9] A frog antioxidant peptide protects against myocardial ischemia reperfusion injury in rats
    Lin, Zhi
    Jiang, Yongliang
    Yang, Ping
    Sun, Lin
    Lu, Di
    ALL LIFE, 2020, 13 (01) : 45 - 53
  • [10] ER stress-induced apoptosis: A novel therapeutic target in myocardial ischemia and reperfusion injury
    Wang, Jichun
    Hu, Xiaorong
    Jiang, Hong
    INTERNATIONAL JOURNAL OF CARDIOLOGY, 2016, 214 : 234 - 235