Exogenous GDF11 attenuates non-canonical TGF- signaling to protect the heart from acute myocardial ischemia-reperfusion injury

被引:57
|
作者
Su, Hsing-Hui [1 ]
Liao, Jiuan-Miaw [2 ,3 ]
Wang, Yi-Hsin [4 ]
Chen, Ke-Min [5 ]
Lin, Chia-Wei [6 ]
Lee, I-Hui [7 ,8 ]
Li, Yi-Ju [9 ,10 ]
Huang, Jing-Yang [4 ,11 ]
Tsai, Shen Kou [12 ]
Yen, Jiin-Cherng [1 ]
Huang, Shiang-Suo [4 ,13 ,14 ]
机构
[1] Natl Yang Ming Univ, Sch Med, Dept & Inst Pharmacol, 155,Sec 2,Lih Nong St, Taipei 11221, Taiwan
[2] Chung Shan Med Univ, Dept Physiol, Taichung, Taiwan
[3] Chung Shan Med Univ Hosp, Taichung, Taiwan
[4] Chung Shan Med Univ, Inst Med, Taichung, Taiwan
[5] Chung Shan Med Univ, Dept Parasitol, Taichung, Taiwan
[6] Med Coll Chung Shan Med Univ, Inst Biochem Microbiol & Immunol, Taichung, Taiwan
[7] Taipei Vet Gen Hosp, Dept Neurol, Taipei, Taiwan
[8] Natl Yang Ming Univ, Inst Brain Sci, Taipei, Taiwan
[9] Chung Shan Med Univ, Dept Pathol, Taichung, Taiwan
[10] Chung Shan Med Univ Hosp, Dept Pathol, Taichung, Taiwan
[11] Chung Shan Med Univ Hosp, Dept Med Res, Taichung, Taiwan
[12] Cheng Hsin Gen Hosp, 45 Cheng Hsin St, Taipei, Taiwan
[13] Chung Shan Med Univ, Dept Pharmacol, 110,Sec 1,Jianguo N Rd, Taichung 402, Taiwan
[14] Chung Shan Med Univ Hosp, Dept Pharm, 110,Sec 1,Jianguo N Rd, Taichung 402, Taiwan
关键词
Growth differentiation factor 11; Transforming growth factor beta 1; Myocardial ischemia-reperfusion; Smad2/3; TGF-beta non-canonical pathway; DIFFERENTIATION FACTOR 11; GENE-TRANSFER IMPROVES; OXIDATIVE STRESS; CELL-DEATH; INFARCTION; AUTOPHAGY; GROWTH; ISCHEMIA/REPERFUSION; ACTIVATION; MECHANISMS;
D O I
10.1007/s00395-019-0728-z
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor beta 1 (TGF-1) superfamily that reverses age-related cardiac hypertrophy, improves muscle regeneration and angiogenesis, and maintains progenitor cells in injured tissue. Recently, targeted myocardial delivery of the GDF11 gene in aged mice was found to reduce heart failure and enhance the proliferation of cardiac progenitor cells after myocardial ischemia-reperfusion (I-R). No investigations have as yet explored the cardioprotective effect of exogenous recombinant GDF11 in acute I-R injury, despite the convenience of its clinical application. We sought to determine whether exogenous recombinant GDF11 protects against acute myocardial I-R injury and investigate the underlying mechanism in Sprague-Dawley rats. We found that GDF11 reduced arrhythmia severity and successfully attenuated myocardial infarction; GDF11 also increased cardiac function after I-R, enhanced HO-1 expression and decreased oxidative damage. GDF11 activated the canonical TGF- signaling pathway and inactivated the non-canonical pathways, ERK and JNK signaling pathways. Moreover, administration of GDF11 prior to reperfusion protected the heart from reperfusion damage. Notably, pretreatment with the activin-binding protein, follistatin (FST), inhibited the cardioprotective effects of GDF11 by blocking its activation of Smad2/3 signaling and its inactivation of detrimental TGF- signaling. Our data suggest that exogenous GDF11 has cardioprotective effects and may have morphologic and functional recovery in the early stage of myocardial I-R injury. GDF11 may be an innovative therapeutic approach for reducing myocardial I-R injury.
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页数:16
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