Protectin D1 alleviates cardiac ischemia-reperfusion injury in rats by up-regulating GPR37/JNK/PPAR-γ signaling pathway in cardiac macrophages

Yalin ZENG; Qin ZHOU; Qingsong XIONG; Yunqing CHEN

doi:10.16016/j.1000-5404.201903197

您当前的位置：

首页 >

文章列表页 >

Protectin D1 alleviates cardiac ischemia-reperfusion injury in rats by up-regulating GPR37/JNK/PPAR-γ signaling pathway in cardiac macrophages

Basic Medicine | 更新时间：2026-01-09

- Protectin D1 alleviates cardiac ischemia-reperfusion injury in rats by up-regulating GPR37/JNK/PPAR-γ signaling pathway in cardiac macrophages
- Journal of Third Military Medical University Vol. 41, Issue 16, Pages: 1511-1519(2019)
- 作者机构：
  
  400010 重庆，重庆医科大学附属第二医院心内科
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(8157070581)
- DOI：10.16016/j.1000-5404.201903197
  CLC： R542.2; R963; R977.6
- Received：25 March 2019，
  
  Revised：2019-05-23，
  
  Published：30 August 2019
- 稿件说明：
移动端阅览
Yalin ZENG, Qin ZHOU, Qingsong XIONG, et al. Protectin D1 alleviates cardiac ischemia-reperfusion injury in rats by up-regulating GPR37/JNK/PPAR-γ signaling pathway in cardiac macrophages[J]. Journal of Third Military Medical University, 2019, 41(16): 1511-1519.
DOI：

Yalin ZENG, Qin ZHOU, Qingsong XIONG, et al. Protectin D1 alleviates cardiac ischemia-reperfusion injury in rats by up-regulating GPR37/JNK/PPAR-γ signaling pathway in cardiac macrophages[J]. Journal of Third Military Medical University, 2019, 41(16): 1511-1519. DOI： 10.16016/j.1000-5404.201903197.

摘要

目的

探讨保护素(protectin D1

PD1)经GPR37/JNK/PPAR-γ通路减轻心脏缺血再灌注损伤的机制。

方法

6~8周雄性SD大鼠60只(体质量180~220 g)，于术前3日每日经腹腔注射PD1 100 nmol/L或等量生理盐水后，建立大鼠心脏缺血再灌注损伤模型，分为4组：假手术组；缺血再灌注组(IR组)；IR+PD1组；IR+PD1+CB组。各组大鼠于术后6 h、24 h、48 h、14 d采集大鼠心脏标本和血液标本，并分离心脏巨噬细胞蛋白。检测心脏病理改变、心肌酶谱改变、心肌纤维化程度、血清炎症因子表达、心肌细胞吞噬功能、细胞极性改变、上清液炎症因子表达、GPR37/JNK/PPAR-γ信号通路表达。

结果

PD1干预后，大鼠心脏病理改变显著下降、心肌酶谱表达下降(

0.05)，血清IL-1β(86.6±22.4)U/L、TNF-α(89.4±18.2)U/L、IL-6(76.7±15.2)U/L表达下降，IL-10(87.6±18.4)U/L、TGF-β(112.7±22.6)U/L表达升高(

0.05)；PD1处理心脏巨噬细胞后，心脏巨噬细胞对凋亡细胞吞噬增高(

0.05)，M2型极化增加(

0.05)，上清液中IL-1β(109.5±21.6) U/L、TNF-α(95.4±17.8) U/L、IL-6(134.2±27.1) U/L表达下降，IL-10(158.4±31.8)U/L、TGF-β(149.6±27.6)U/L表达升高(

0.05)，GPR37(2.14±0.31)、IRE1α (2.67±0.44)、ATF6 (1.97±0.37)、PERK (2.27±0.67)、p-JNK (1.95±0.39)、PPAR-γ (1.87±0.67)表达上升(

0.05)。

结论

PD1能够减轻心脏缺血再灌注损伤程度，其机制可能是经上调GPR37/JNK/PPAR-γ通路的活性，促进心脏巨噬细胞吞噬功能、M2型极化、抑炎因子表达。

Abstract

Objective

To investigate the mechanism by which protectin D1 (PD1) alleviates cardiac ischemia-reperfusion (IR) injury

via

GPR37/JNK/PPAR-γ signaling pathway.

Methods

Male adult SD rats (6-8 weeks old) were randomly divided into sham-operation group

IR group

IR+PD1 group

and IR+PD1+ cytochalasin B (CB) group. In the latter 3 groups

the rats were subjected to daily intraperitoneal injections of normal saline

PD1 (100 nmol/L)

or PD1 and CB for consecutive 3 days before establishment of cardiac IR injury models. At 6

and 48 h and at 2 weeks after the surgery

the hearts and blood samples were collected from each group

and the cardiac macrophages were isolated and cultured. The cardiac pathologies

changes in cardiac enzyme profile

cardiac fibrosis

serum inflammatory factors

phagocytic function of the cardiac macrophages

changes in the cell polarity

and the expressions of inflammatory factors and GPR37/JNK/ PPAR-γ signaling pathway in cultured cardiac macrophages were detected.

Results

In the rats with cardiac IR injury

PD1 treatment significantly alleviated the cardiac pathologies

lowered the expressions of the cardiac enzymes (

0.05)

decreased the serum levels of IL-1β

TNF-α

and IL-6 while increased the serum levels of IL-10 and TGF-β (

0.05). In the cultured cardiac macrophages

PD1 treatment significantly enhanced their phagocytosis of the apoptotic cells (

0.05) and M2-type polarization (

0.05)

decreased the expressions of IL-1β

TNF-α

IL-6

and increased the expressions of IL-10 and TGF-β (

0.05) and the expressions of GPR37

IRE1α

ATF6

PERK

p-JNK

and PPAR-γ (

0.05).

Conclusion

PD1 can alleviate cardiac IR injury in rats possibly by up-regulating the GPR37/JNK/PPAR-γ signaling pathway to enhance the phagocytic activity of the cardiac macrophages and the expressions of the anti-inflammatory factors.

关键词

Keywords

references

DAMMAN P, VAN'T HOF A W, TEN BERG J M, et al . 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: comments from the Dutch ACS working group[J ] . Neth Heart J, 2017, 25(3): 181-185. DOI: 10.1007/s12471-016-0939-y.

FORMIGLI L, MANNESCHI L I, NEDIANI C, et al . Are macrophages involved in early myocardial reperfusion injury?[J ] . Ann Thorac Surg, 2001, 71(5): 1596-1602. DOI: 10.1016/s0003-4975(01)02400-6.

DE COUTO G, LIU W X, TSELIOU E, et al . Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction[J ] . J Clin Invest, 2015, 125(8): 3147-3162. DOI: 10.1172/JCI81321.

TIAN Y K, PIRAS B A, KRON I L, et al . Adenosine 2B receptor activation reduces myocardial reperfusion injury by promoting anti-inflammatory macrophages differentiation via PI 3 K/Akt pathway[J ] . Oxid Med Cell Longev, 2015, 2015: 585297. DOI: 10.1155/2015/585297..

CHENG Y Y, YANG C B, LUO D, et al . N-propargyl caffeamide skews macrophages towards a resolving M2-like phenotype against myocardial ischemic injury via activating Nrf2/HO-1 pathway and inhibiting NF-κB pathway[J ] . Cell Physiol Biochem, 2018, 47(6): 2544-2557. DOI: 10.1159/000491651..

BANG S S, XIE Y K, ZHANG Z J, et al . GPR37 regulates macrophage phagocytosis and resolution of inflammatory pain[J ] . J Clin Invest, 2018, 128(8): 3568-3582. DOI: 10.1172/J CI99888.

KAPOOR N, NIU J, SAAD Y, et al . Transcription factors STAT6 and KLF4 implement macrophage polarization via the dual catalytic powers of MCPIP[J ] . J Immunol, 2015, 194: 6011-6023.DOI: 10.4049/jimmunol.1402797..

WIRES E S, TRYCHTA K A, BÄCK S, et al . High fat diet disrupts endoplasmic reticulum calcium homeostasis in the rat liver[J ] . J Hepatol, 2017, 67(5): 1009-1017. DOI: 10.1016/j.jhep.2017.05.023.

OH J, RIEKA E, WENG S, et al . Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation[J ] . J Biol Chem, 2012, 287(15): 11629-11641. DOI: 10.1074/jbc.M111.338673.

XU Z Z, LIU X J, BERTA T, et al . Neuroprotectin/protectin D1 protects against neuropathic pain in mice after nerve trauma[J ] . Ann Neurol, 2013, 74(3): 490-495. DOI: 10.1002/ana.23928.

CARLSON S, HELTERLINE D, ASBE L, et al . Cardiac macrophages adopt profibrotic/M2 phenotype in infarcted hearts: Role of urokinase plasminogen activator[J ] . J Mol Cell Cardiol, 2017, 108: 42-49. DOI: 10.1016/j.yjmcc.2016.05.016.

SUN E, GAO Y, CHEN J, et al . Allograft tolerance induced by donor apoptotic lymphocytes requires phagocytosis in the recipient[J ] . Cell Death Differ, 2004, 11(12): 1258-1264. DOI: 10.1038/sj.cdd.4401500.

MOZAFFARIAN D, BENJAMIN E J, GO A S, et al . Heart disease and stroke statistics—2015 update[J ] . Circulation, 2015, 131: e29-e322. DOI: 10.1161/CIR.0000000000000152.

TURER A T, HILL J A. Pathogenesis of myocardial ischemia-reperfusion injury and rationale for therapy[J]. Am J Cardiol, 2010, 106(3): 360-368. DOI: 10.1016/j.amjcard.2010.03.032.

LIU Y C, ZOU X B, CHAI Y F, et al . Macrophage polarization in inflammatory diseases[J ] . Int J Biol Sci, 2014, 10(5): 520-529. DOI: 10.7150/ijbs.8879.

CHANG C, JI Q W, WU B W, et al . Chemerin15-ameliorated cardiac ischemia-reperfusion injury is associated with the induction of alternatively activated macrophages[J ] . Mediators Inflamm, 2015, 2015: 563951. DOI: 10.1155/2015/563951.

YUE Y, YANG X, FENG K N, et al . M2b macrophages reduce early reperfusion injury after myocardial ischemia in mice: A predominant role of inhibiting apoptosis via A20[J ] . Int J Cardiol, 2017, 245: 228-235. DOI: 10.1016/j.ijcard.2017.07.085..

LIN Y, ZHAO J L, ZHENG Q J, et al . Notch signaling modulates macrophage polarization and phagocytosis through direct suppression of signal regulatory protein α expression[J ] . Front Immunol, 2018, 9: 1744. DOI: 10.3389/fimmu.2018.01744.

CUNHAL D, YANG M, CARTER R, et al . LC 3 -associated phagocytosis in myeloid cells promotes tumor immune tolerance[J ] . Cell, 2018, 175(2): 429-441.e16. DOI: 10.1016/j.cell.2018.08.061..

SHINDE R, HEZAVEH K, HALABY M J, et al . Apoptotic cell-induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans[J ] . Nat Immunol, 2018, 19(6): 571-582. DOI: 10.1038/s41590-018-0107-1.

PARKJ K,SHAO M J, KIM M Y, et al . An endoplasmic reticulum protein, Nogo-B, facilitates alcoholic liver disease through regulation of Kupffer cell polarization[J ] . Hepatology, 2017, 65(5): 1720-1734. DOI: 10.1002/hep.29051.

XU X, WANG M, LI J Z, et al . Tauroursodeoxycholic acid alleviates hepatic ischemia reperfusion injury by suppressing the function of Kupffer cells in mice[J ] . Biomed Pharmacother, 2018, 106: 1271-1281. DOI: 10.1016/j.biopha.

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

No data

Related Author

No data

Related Institution

No data

⁰