Netrin-1 attenuates cardiac ischemia reperfusion injury and generates alternatively activated macrophages.
Ischemia reperfusion (IR) injury is a major issue in cardiac transplantation and inflammatory processes play a major role in myocardial IR injury. Netrin-1 is a laminin-related protein identified as a neuronal guidance cue and netrin-1 expressed outside the nervous system inhibits migration of leukocytes in vitro and in vivo and attenuates inflammation-mediated tissue injury. In our study, hearts of C57BL/6 mice were flushed and stored in cold Bretschneider solution for 8 h and then transplanted into syngeneic recipient. We found that netrin-1 decreased cardiomyocyte apoptosis and recruitment of neutrophils and macrophages. Troponin T (TnT) production on 24 h after myocardial IR injury was reduced by netrin-1 administration. Cardiac output at 60 mmHg of afterload pressure was significantly increased in hearts with netrin-1 administration (IR + Netrin-1: 59.9 ± 5.78 ml/min; IR: 26.2 ± 4.3 ml/min; P < 0.05). Netrin-1 treatment increased expression of the alternatively activated macrophage (AAM) markers arginase-1 (Arg-1) and mannose receptor (MR) and promoted proliferator-activated receptor γ (PPARγ) expression in cardiac allograft. Furthermore, decreased TnT expression and reduced allograft infiltration of neutrophils and monocytes/macrophages by netrin-1 was abolished with addition of PPARγ antagonist. In conclusion, netrin-1 attenuates cardiac IR injury and generates AAM which contributes to the protective effect of netrin-1.
Department of Gynaecology and Obstetrics, Xiangyan Central Hospital, Hubei University of Arts and Science, Jinzhou Road 136#, Xiangyang, 441021, Hubei, China.
Xiaogang
X
Mao
Hui
H
Xing
Aihua
A
Mao
Hong
H
Jiang
Li
L
Cheng
Yun
Y
Liu
Xiaozhen
X
Quan
Lin
L
Li
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001119:Arginase / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D016027:Heart Transplantation / Q000009:adverse effects*; D006439:Hemodynamics / Q000187:drug effects; D037181:Lectins, C-Type / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009414:Nerve Growth Factors / Q000494:pharmacology*; D000075388:Netrin-1; D020556:Neutrophil Infiltration / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D020107:Troponin T / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000494:pharmacology*
D015415:Biomarkers; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D047495:PPAR gamma; D020011:Protective Agents; D011956:Receptors, Cell Surface; D020107:Troponin T; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; C544448:Arg1 protein, mouse; D001119:Arginase