Dataset Information

Haematopoietic and cardiac GPR55 synchronize post-myocardial infarction remodelling.

ABSTRACT: While classical cannabinoid receptors are known to crucially impact on myocardial infarction (MI) repair, a function of the cannabinoid-sensitive receptor GPR55 herein is poorly understood. We investigated the role of GPR55 in cardiac physiology and post-MI inflammation and remodelling. Global GPR55-/- and wildtype (WT) mice were basally characterized or assigned to 1, 3 or 28 days permanent MI and subsequently analysed via pro-inflammatory and pro-hypertrophic parameters. GPR55-/- deficiency was basally associated with bradycardia, increased diastolic LV volume and sarcomere length and a subtle inflammatory phenotype. While infarct size and myeloid cell infiltration were unaffected by GPR55 depletion, acute cardiac chemokine production was prolonged post-MI. Concurrently, GPR55-/- hearts exhibited a premature expansion of pro-reparative and phagocytic macrophages paralleled by early up-regulation of extracellular matrix (ECM) factors 3 days post-MI, which could be mimicked by sole haematopoietic GPR55 depletion. Moreover, global GPR55 deficiency mitigated MI-induced foetal gene re-programming and cardiomyocyte hypertrophy, culminating in aggravated LV dilatation and infarct expansion. GPR55 regulates cardiac homeostasis and ischaemia responses by maintaining adequate LV filling and modulating three crucial processes post-MI: wound healing kinetics, cardiomyocyte hypertrophy and maladaptive remodelling.

SUBMITTER: Puhl SL

PROVIDER: S-EPMC8277802 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Haematopoietic and cardiac GPR55 synchronize post-myocardial infarction remodelling.

Puhl Sarah-Lena SL Hilby Michael M Kohlhaas Michael M Keidel Linus M LM Jansen Yvonne Y Hristov Michael M Schindler Jakob J Maack Christoph C Steffens Sabine S

Scientific reports 20210713 1

While classical cannabinoid receptors are known to crucially impact on myocardial infarction (MI) repair, a function of the cannabinoid-sensitive receptor GPR55 herein is poorly understood. We investigated the role of GPR55 in cardiac physiology and post-MI inflammation and remodelling. Global GPR55-/- and wildtype (WT) mice were basally characterized or assigned to 1, 3 or 28 days permanent MI and subsequently analysed via pro-inflammatory and pro-hypertrophic parameters. GPR55-/- deficiency wa ...[more]

PMID: 34257332

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Project description:BackgroundMyocardial infarction (MI) and subsequent ischaemic cardiomyopathy (ICM) are the primary causes of heart failure. Inter-α trypsin inhibitor heavy chain 5 (ITIH5) is an extracellular matrix (ECM) protein and has been identified as a myocardial marker of ICM. However, its diagnostic value in patients with ICM and its function and molecular mechanism in regulating cardiac repair and remodelling after MI remain unknown.MethodsThree microarray datasets including 117 ICM and 152 non-failing (NF) myocardial tissue samples were merged and analysed. Peripheral blood and clinical information were collected from 53 patients with ICM and 40 NF controls. The effects of ITIH5 on cellular interactions and cardiac remodelling was studied using ITIH5 RNAi adeno-associated virus and mouse MI model in vivo and in fibroblast-macrophage co-culture model in vitro.ResultsITIH5 was upregulated in the myocardial tissue and peripheral blood of patients with ICM and could be an independent risk factor for ICM. Experiments in mice suggested that ITIH5 promotes cardiac fibrotic remodelling at all phases after MI. Downregulation of ITIH5 increased the risk of death within 7 d after MI but inhibited ventricular remodelling and improved cardiac function on the long-term. ITIH5 promotes the primary cardiac fibroblasts (CFs) proliferation, migration, and improves survival rather than activiation. Morover, ITIH5 directly promotes macrophage tissue infiltration, maturation, and profibrotic phenotype transformation, thereby promoting fibrotic remodelling. By using fibroblast-macrophage co-culture model, we demonstrated ITIH5 enhanced the fibroblast/macrophage crosstalk manifest as macrophage profibrotic phenotype transformation and CFs activation, mainly by enhancing the hyaluronan stability, the ability of ITIH5 to bind macrophage CD44 receptors and the downstream activation of the signal transduction and activator of transcription 3 pathway in macrophages.ConclusionsITIH5 could be used as a diagnostic marker for ICM. Moreover, ITIH5 expression was upregulated after MI, which accelerated ECM-fibroblast-macrophage interaction, thereby promoting macrophage profibrotic phenotype transformation, CFs activation, and cardiac fibrotic remodelling.

Project description:Background: Myocardial infarction (MI) and subsequent ischaemic cardiomyopathy (ICM) are the primary causes of heart failure. Inter-α trypsin inhibitor heavy chain 5 (ITIH5) is an ECM protein and has been identified as a myocardial marker of ICM. However, its diagnostic value in patients with ICM and its function and molecular mechanism in regulating cardiac repair and remodelling after MI remain unknown. Methods: Three microarray datasets including 117 ICM and 152 non-failing (NF) myocardial tissue samples were merged and analysed. Peripheral blood and clinical information were collected from 53 patients with ICM and 40 NF controls. The effects of ITIH5 on cellular interactions and cardiac remodelling was studied using ITIH5 RNAi adeno-associated virus and mouse MI model in vivo and in fibroblast–macrophage co-culture model in vitro. Results: ITIH5 was upregulated in the myocardial tissue and peripheral blood of patients with ICM and could be an independent risk factor for ICM. Experiments in mice suggested that ITIH5 promotes cardiac fibrotic remodelling at all phases after MI. Downregulation of ITIH5 increased the risk of death within 7 d after MI but inhibited ventricular remodelling and improved cardiac function on the long-term. ITIH5 promotes the primary cardiac fibroblasts (CFs) proliferation, migration, and improves survival rather than activiation. Morover, ITIH5 directly promotes macrophage tissue infiltration, maturation, and profibrotic phenotype transformation, thereby promoting fibrotic remodelling. By using fibroblast–macrophage co-culture model, we demonstrated ITIH5 enhanced the fibroblast/macrophage crosstalk manifest as macrophage profibrotic phenotype transformation and CFs activation, mainly by enhancing the hyaluronan stability, the ability of ITIH5 to bind macrophage CD44 receptors and the downstream activation of the signal transduction and activator of transcription 3 pathway in macrophages. Conclusions: ITIH5 could be used as a diagnostic marker for ICM. Moreover, ITIH5 expression was upregulated after MI, which accelerated ECM-fibroblast-macrophage interaction, thereby promoting macrophage profibrotic phenotype transformation, CFs activation, and cardiac fibrotic remodelling.

Dataset Information

Haematopoietic and cardiac GPR55 synchronize post-myocardial infarction remodelling.

Publications

Haematopoietic and cardiac GPR55 synchronize post-myocardial infarction remodelling.

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