Activation of E-prostanoid 3 receptor in macrophages facilitates cardiac healing after myocardial infarction

Juan Tang; Yujun Shen; Guilin Chen; Qiangyou Wan; Kai Wang; Jian Zhang; Jing Qin; Guizhu Liu; Shengkai Zuo; Bo Tao; Yu Yu; Junwen Wang; Michael Lazarus; Ying Yu

doi:10.1038/ncomms14656

Activation of E-prostanoid 3 receptor in macrophages facilitates cardiac healing after myocardial infarction

Nat Commun. 2017 Mar 3:8:14656. doi: 10.1038/ncomms14656.

Authors

Juan Tang^{1

2}, Yujun Shen², Guilin Chen², Qiangyou Wan¹, Kai Wang¹, Jian Zhang^{1

2}, Jing Qin^{3

4}, Guizhu Liu¹, Shengkai Zuo¹, Bo Tao¹, Yu Yu¹, Junwen Wang^{3

5

6}, Michael Lazarus⁷, Ying Yu^{1

2}

Affiliations

¹ Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
² Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
³ Center for Genomic Sciences, LKS Faculty of Medicine, The University of Hong Kong, 5 Sassoon Road, Hong Kong, SAR 999077, China.
⁴ School of Life Science, Chinese University of Hong Kong, Hong Kong, SAR 999077, China.
⁵ Division of Biomedical Statistics and Informatics, Center for Individualized Medicine, Mayo Clinic, Scottsdale, Arizona 85259, USA.
⁶ Department of Biomedical Informatics, Arizona State University, Scottsdale, Arizona 85259, USA.
⁷ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba City, Ibaraki 305-8575, Japan.

Abstract

Two distinct monocyte (Mo)/macrophage (Mp) subsets (Ly6C^low and Ly6C^high) orchestrate cardiac recovery process following myocardial infarction (MI). Prostaglandin (PG) E₂ is involved in the Mo/Mp-mediated inflammatory response, however, the role of its receptors in Mos/Mps in cardiac healing remains to be determined. Here we show that pharmacological inhibition or gene ablation of the Ep3 receptor in mice suppresses accumulation of Ly6C^low Mos/Mps in infarcted hearts. Ep3 deletion in Mos/Mps markedly attenuates healing after MI by reducing neovascularization in peri-infarct zones. Ep3 deficiency diminishes CX3C chemokine receptor 1 (CX3CR1) expression and vascular endothelial growth factor (VEGF) secretion in Mos/Mps by suppressing TGFβ1 signalling and subsequently inhibits Ly6C^low Mos/Mps migration and angiogenesis. Targeted overexpression of Ep3 receptors in Mos/Mps improves wound healing by enhancing angiogenesis. Thus, the PGE₂/Ep3 axis promotes cardiac healing after MI by activating reparative Ly6C^low Mos/Mps, indicating that Ep3 receptor activation may be a promising therapeutic target for acute MI.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CX3C Chemokine Receptor 1 / genetics
CX3C Chemokine Receptor 1 / metabolism
Cell Movement / genetics
Cells, Cultured
Gene Expression
Macrophages / metabolism*
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Myocardial Infarction / genetics
Myocardial Infarction / metabolism*
Myocardial Infarction / physiopathology
Myocardium / metabolism*
Myocardium / pathology
Receptors, Prostaglandin E, EP3 Subtype / genetics
Receptors, Prostaglandin E, EP3 Subtype / metabolism*
Recovery of Function
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism
Ventricular Remodeling / physiology

Substances

CX3C Chemokine Receptor 1
Cx3cr1 protein, mouse
Receptors, Prostaglandin E, EP3 Subtype
Vascular Endothelial Growth Factor A

Grants and funding

P30 CA015083/CA/NCI NIH HHS/United States