M1-like macrophage-derived exosomes suppress angiogenesis and exacerbate cardiac dysfunction in a myocardial
Shaojun Liu1, Jing Chen2, Jian Shi2
1Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, Guangdong, People's Republic of China. shaojunliu@gzhmu.edu.cn.
Abstract:
The roles and the underlying mechanisms of M1-type macrophages in angiogenesis and postmyocardial infarction (MI) cardiac repair have remained unclear. In this study, we investigated the role of M1-like macrophage-derived exosomes in a MI microenvironment. We found that the proinflammatory M1-like-type macrophages released an extensive array of proinflammatory exosomes (M1-Exos) after MI. M1-Exos exerted an anti-angiogenic effect and accelerated MI injury. They also exhibited highly expressed proinflammatory miRNAs, such as miR-155. miR-155 was transferred to endothelial cells (ECs), leading to the inhibition of angiogenesis and cardiac dysfunction by downregulating its novel target genes, including Rac family small GTPase 1 (RAC1), p21 (RAC1)-activated kinase 2 (PAK2), Sirtuin 1 (Sirt1), and protein kinase AMP-activated catalytic subunit alpha 2 (AMPKα2). M1-Exos depressed Sirt1/AMPKα2-endothelial nitric oxide synthase and RAC1-PAK2 signaling pathways by simultaneously targeting the five molecule nodes (genes), reduced the angiogenic ability of ECs, aggravated myocardial injury, and restrained cardiac healing. The elucidation of this mechanism provides novel insights into the functional significance of M1 macrophages and their derived exosomes on angiogenesis and cardiac repair. This mechanism can be used as a novel potential therapeutic approach for the prevention and treatment of MI.
Insights
Proinflammatory M1 macrophage-derived exosomes (M1-Exos) impair cardiac repair after myocardial infarction (MI). M1-Exos, particularly miR-155, inhibit angiogenesis and worsen heart injury by targeting key signaling pathways.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cellular and Molecular Medicine
Background:
- The role of M1 macrophages in cardiac repair post-myocardial infarction (MI) is not fully understood.
- Investigating the mechanisms by which M1 macrophages influence angiogenesis and healing after MI is crucial.
Purpose of the Study:
- To elucidate the role of M1 macrophage-derived exosomes (M1-Exos) in the MI microenvironment.
- To determine the impact of M1-Exos on angiogenesis and cardiac repair.
Main Methods:
- Analysis of M1-Exos released by M1-like macrophages in a MI model.
- Investigation of M1-Exos' effect on endothelial cells (ECs) and cardiac function.
- Identification of specific microRNAs (miRNAs) and target genes within M1-Exos.
Main Results:
- M1-like macrophages release proinflammatory M1-Exos post-MI.
- M1-Exos exhibit anti-angiogenic properties and exacerbate MI injury.
- miR-155 within M1-Exos downregulates RAC1, PAK2, Sirt1, and AMPKα2 in ECs, inhibiting angiogenesis and cardiac healing.
Conclusions:
- M1-Exos, via miR-155, disrupt angiogenesis and cardiac repair by targeting multiple signaling pathways.
- Understanding this mechanism offers potential therapeutic targets for MI treatment.
- M1 macrophages and their exosomes play a significant role in post-MI cardiac remodeling.
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