Early treatment with Resolvin E1 facilitates myocardial recovery from ischaemia in mice

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Abstract

<div class="section"> <a class="named-anchor" id="bph14041-sec-0001">  </a> <h5 class="section-title" id="d5083007e477">Background and Purpose</h5> <p id="d5083007e479">An appropriate inflammatory response is necessary for cardiac healing after acute myocardial infarction (MI). Resolvin E1 (RvE1) is an anti‐inflammatory and pro‐resolution lipid mediator derived from eicosapentaenoic acid. Here we have investigated the effects of RvE1 on the recovery of cardiac function after MI in mice. </p> </div><div class="section"> <a class="named-anchor" id="bph14041-sec-0002">  </a> <h5 class="section-title" id="d5083007e482">Experimental Approach</h5> <p id="d5083007e484">Acute MI was induced by surgical ligation of the left anterior descending artery in male C57BL/6 mice. RvE1 (5 ng·g <sup>−1</sup>·day <sup>−1</sup>; i.p.) was given to mice at different times following MI. Cardiac function was monitored by transthoracic echocardiography at days 3, 7 and 14 after MI. Effects of RvE1 on the migration of subpopulations of monocytes/macrophages (Mos/Mps, Ly6C <sup>hi</sup> and Ly6C <sup>low</sup>) were examined by flow cytometry and transwell assay. </p> </div><div class="section"> <a class="named-anchor" id="bph14041-sec-0003">  </a> <h5 class="section-title" id="d5083007e499">Key Results</h5> <p id="d5083007e501">RvE1 administration from days 1 to 7 post‐MI improved cardiac function, whereas treatment from days 7 to 14 markedly inhibited recovery of cardiac function. Early treatment with RvE1 post‐MI suppressed the infiltration of dominant Ly6C <sup>hi</sup> Mos/Mps and secretion of pro‐inflammatory cytokines in injured hearts, which protected cardiomyocytes against apoptosis in the peri‐infarct zones. Contrastingly, treatment with RvE1 1 week after MI decreased infiltration of Ly6C <sup>low</sup> Mos/Mps and expression of pro‐angiogenic factors in cardiac tissue, consequently reducing neovascularization in the peri‐infarct zones. Additionally, RvE1 inhibited Mp migration by activating ChemR23 receptors. </p> </div><div class="section"> <a class="named-anchor" id="bph14041-sec-0004">  </a> <h5 class="section-title" id="d5083007e510">Conclusion and Implications</h5> <p id="d5083007e512">Treatment with RvE1 during the initial 7 days after MI facilitated cardiac healing by suppressing pro‐inflammatory cytokine secretion, indicating that RvE1 may serve as an early therapeutic agent for acute MI. </p> </div><div class="section"> <a class="named-anchor" id="bph14041-sec-0050">  </a> <h5 class="section-title" id="d5083007e515">Linked Articles</h5> <p id="d5083007e517">This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit <a data-untrusted="" href="http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc" id="d5083007e519" target="xrefwindow">http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc</a> </p> </div>

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Macrophages are required for neonatal heart regeneration.

Arin B Aurora, Enzo Porrello, Wei Tan … (2014)

Myocardial infarction (MI) leads to cardiomyocyte death, which triggers an immune response that clears debris and restores tissue integrity. In the adult heart, the immune system facilitates scar formation, which repairs the damaged myocardium but compromises cardiac function. In neonatal mice, the heart can regenerate fully without scarring following MI; however, this regenerative capacity is lost by P7. The signals that govern neonatal heart regeneration are unknown. By comparing the immune response to MI in mice at P1 and P14, we identified differences in the magnitude and kinetics of monocyte and macrophage responses to injury. Using a cell-depletion model, we determined that heart regeneration and neoangiogenesis following MI depends on neonatal macrophages. Neonates depleted of macrophages were unable to regenerate myocardia and formed fibrotic scars, resulting in reduced cardiac function and angiogenesis. Immunophenotyping and gene expression profiling of cardiac macrophages from regenerating and nonregenerating hearts indicated that regenerative macrophages have a unique polarization phenotype and secrete numerous soluble factors that may facilitate the formation of new myocardium. Our findings suggest that macrophages provide necessary signals to drive angiogenesis and regeneration of the neonatal mouse heart. Modulating inflammation may provide a key therapeutic strategy to support heart regeneration.

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Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms.

Charles Serhan (2017)

Practitioners of ancient societies from the time of Hippocrates and earlier recognized and treated the signs of inflammation, heat, redness, swelling, and pain with agents that block or inhibit proinflammatory chemical mediators. More selective drugs are available today, but this therapeutic concept has not changed. Because the acute inflammatory response is host protective to contain foreign invaders, much of today's pharmacopeia can cause serious unwanted side effects, such as immune suppression. Uncontrolled inflammation is now considered pathophysiologic and is associated with many widely occurring diseases such as cardiovascular disease, neurodegenerative diseases, diabetes, obesity, and asthma, as well as classic inflammatory diseases (e.g., arthritis and periodontal diseases). The inflammatory response, when self-limited, produces a superfamily of chemical mediators that stimulate resolution of the response. Specialized proresolving mediators (SPMs), identified in recent years, are endogenous mediators that include the n-3-derived families resolvins, protectins, and maresins, as well as arachidonic acid-derived (n-6) lipoxins, which promote resolution of inflammation, clearance of microbes, reduction of pain, and promotion of tissue regeneration via novel mechanisms. Aspirin and statins have a positive impact on these resolution pathways, producing epimeric forms of specific SPMs, whereas other drugs can disrupt timely resolution. In this article, evidence from recent human and preclinical animal studies is reviewed, indicating that SPMs are physiologic mediators and pharmacologic agonists that stimulate resolution of inflammation and infection. The findings suggest that it is time to challenge current treatment practices-namely, using inhibitors and antagonists alone-and to develop immunoresolvents as agonists to test resolution pharmacology and their role in catabasis for their therapeutic potential.-Serhan, C. N. Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms.

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Fractalkine Preferentially Mediates Arrest and Migration of CD16+ Monocytes

Petronela Ancuta, Ravi Rao, Ashlee V Moses … (2003)

CD16+ monocytes represent 5–10% of peripheral blood monocytes in normal individuals and are dramatically expanded in several pathological conditions including sepsis, human immunodeficiency virus 1 infection, and cancer. CD16+ monocytes produce high levels of proinflammatory cytokines and may represent dendritic cell precursors in vivo. The mechanisms that mediate the recruitment of CD16+ monocytes into tissues remain unknown. Here we investigate molecular mechanisms of CD16+ monocyte trafficking and show that migration of CD16+ and CD16− monocytes is mediated by distinct combinations of adhesion molecules and chemokine receptors. In contrast to CD16− monocytes, CD16+ monocytes expressed high CX3CR1 and CXCR4 but low CCR2 and CD62L levels and underwent efficient transendo-thelial migration in response to fractalkine (FKN; FKN/CX3CL1) and stromal-derived factor 1α (CXCL12) but not monocyte chemoattractant protein 1 (CCL2). CD16+ monocytes arrested on cell surface–expressed FKN under flow with higher frequency compared with CD16− monocytes. These results demonstrate that FKN preferentially mediates arrest and migration of CD16+ monocytes and suggest that recruitment of this proinflammatory monocyte subset to vessel walls via the CX3CR1-FKN pathway may contribute to vascular and tissue injury during pathological conditions.

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Author and article information

Journal

Title: British Journal of Pharmacology

Abbreviated Title: British Journal of Pharmacology

Publisher: Wiley

ISSN: 00071188

Publication date Created: April 2018

Publication date (Print): April 2018

Publication date (Electronic): October 22 2017

Volume: 175

Issue: 8

Pages: 1205-1216

Affiliations

[1 ]Key Laboratory of Food Safety Research, Shanghai Institutes for Biological Sciences; University of Chinese Academy of Sciences, Chinese Academy of Sciences; Shanghai 200031 China

[2 ]Department of Pharmacology, College of Basic Medical Sciences; Tianjin Medical University; Tianjin 300070 China

[3 ]Department of Gastroenterology; Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine; Shanghai 200025 China

[4 ]Department of Cardiology, The First Affiliated Hospital, School of Medicine; Zhejiang University; Hangzhou Zhejiang 310003 China

[5 ]The State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences; Shanghai 200031 China

[6 ]Department of Biomedical and Molecular Sciences; Queen's University; Kingston ON K7L3N6 Canada