C-X-C Motif Chemokine Receptor 4 Blockade Promotes Tissue Repair After Myocardial Infarction by Enhancing Regulatory T Cell Mobilization and Immune-Regulatory Function

Wang, Yong; Dembowsky, Klaus; Chevalier, Éric; Stüve, Philipp; Korf‐Klingebiel, Mortimer; Lochner, Matthias; Napp, L. Christian; Frank, Heike; Brinkmann, E; Kanwischer, Anna; Bauersachs, Johann; Gyöngyösi, Mariann; Sparwasser, Tim; Wollert, Kai C.

doi:10.1161/circulationaha.118.036053

Cited by 95 publications

(82 citation statements)

References 51 publications

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“…We used Real-Time PCR to quantify the mRNA levels of CXCR4 and its ligand, the stromal cell-derived factor 1 (SDF-1), also known as CXCL12. The CXCR4 mRNA levels significantly increased after 7 days ( Figure 6A) and 60 days ( Figure 6B) of MI induction, corroborating previous reports [53,54]. Treatment with HPβCD/Ang-(1-7) reduced the CXCR4 mRNA to its basal levels (similar to Sham) after 7 days ( Figure 6A) and 60 days ( Figure 6B).…”

Section: Validation Of Cxcr4 As a Downstream Effector Of Hpβcd/ang-(1supporting

confidence: 89%

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Angiotensin-(1-7) oral treatment after experimental myocardial infarction leads to downregulation of CXCR4

Gómez‐Mendoza

Marques

Melo‐Braga

et al. 2019

Journal of Proteomics

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Myocardial infarction triggers cellular events that starts with the activation of inflammatory response and fibrogenic pathways involved in cardiac tissue remodeling. Angiotensin-(1-7) (Ang-(1-7)) is an endogenous heptapeptide from the renin-angiotensin system with a cardioprotective role due to its anti-inflammatory and anti-fibrotic activities in cardiac cells. Although the beneficial aspects of Ang-(1-7) in animal models of cardiac ischemia have been reported, the molecular events underlying Ang-(1-7) cardioprotective effect remains elusive. This study investigated the impact of oral treatment with Ang-(1-7) included in hydroxypropyl β-cyclodextrin (HPβCD/Ang-(1-7)) on the cardiac proteome dysregulation due to experimental myocardial infarction. Wistar male rats were submitted to experimental myocardial infarction and treated daily with HPβCD/Ang-(1-7) during 7 days or 60 days by gavage. Our results showed that HPβCD/Ang-(1-7) treatment ameliorates the postinfarction condition due to the modulation of proteins that initially favor the resolution of inflammation and mitochondrial dysfunction. Moreover, this study reported for the first time that Ang-(1-7) treatment after experimental myocardial infarction leads to the downregulation of the C-X-C chemokine receptor type 4 (CXCR4). Significance Myocardial infarction triggers a sequence of cellular and molecular events that starts with an intense inflammatory response that is resolved in the proliferative phase. Prolonged inflammatory phase can lead to adverse cardiac repair and heart failure. In this context, we proposed a post-MI treatment using Ang-(1-7) included in HPβCD and administrated orally. We observed that HPβCD/Ang-(1-7) treatment led to CXCR4 downregulation, highlighting this C-X-C chemokine receptor as a potential therapeutic target for ischemic heart diseases.

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Section: Validation Of Cxcr4 As a Downstream Effector Of Hpβcd/ang-(1supporting

confidence: 89%

“…This event is independent of CXCL12 regulation. Our data confirm CXCR4 as a potential MI biomarker and therapeutic target [51,52,54,68]..…”

Section: Validation Of Cxcr4 As a Downstream Effector Of Hpβcd/ang-(1supporting

confidence: 81%

Angiotensin-(1-7) oral treatment after experimental myocardial infarction leads to downregulation of CXCR4

Gómez‐Mendoza

Marques

Melo‐Braga

et al. 2019

Journal of Proteomics

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“…It might therefore be safe to conclude that the PET/CT approach used in this study could offer a suitable method for monitoring local adaptive immune responses in MI patients. Indeed, a recently published study revealed that CXCR4 plays an important role in controlling T cell trafficking in the context of EMI and thereby influences the healing outcome (65), and these findings provide great mechanistic support for our clinical findings.…”

Section: Methodssupporting

confidence: 82%

Myocardial infarction triggers cardioprotective antigen-specific T helper cell responses

Rieckmann

Delgobo²,

Gaal³

et al. 2019

Journal of Clinical Investigation

129

132

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“…C‐X‐C motif chemokine receptor (CXCR) family is a member of seven‐transmembrane receptors, which exerts chemoattractant effects on leucocytes and other cell types in controlling cell activation and guiding cell movements under basal and inflammatory conditions . There are 8 members of C‐X‐C motif chemokine receptors (CXCR1‐8), which play the critical roles in immune, neurodegenerative and cardiovascular diseases . Recent reports show that several C‐X‐C motif chemokine receptors also play the fundamental roles in the progression of CKD, such as CXCR1, CXCR6 and particularly CXCR4 .…”

Section: Discussionmentioning

confidence: 99%

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

Liu

Feng

Miao

et al. 2020

J Cellular Molecular Medi

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Chronic kidney disease (CKD) has a high prevalence worldwide. Renal fibrosis is the common pathological feature in various types of CKD. However, the underlying mechanisms are not determined. Here, we adopted different CKD mouse models and cultured human proximal tubular cell line to examine the expression of C-X-C motif chemokine receptor 4 (CXCR4) and β-catenin signalling, as well as their relationship in renal fibrosis. In CKD mice and humans with a variety of nephropathies, CXCR4 was dramatically up-regulated in tubules, with a concomitant activation of β-catenin. CXCR4 expression level was positively correlated with the expression of β-catenin target MMP-7. AMD3100, a CXCR4 receptor blocker, and gene knockdown of CXCR4 significantly inhibited the activation of JAK/STAT and β-catenin signalling, protected against tubular injury and renal fibrosis. CXCR4-induced renal fibrosis was inhibited by treatment with ICG-001, an inhibitor of β-catenin signalling. In HKC-8 cells, overexpression of CXCR4 induced activation of β-catenin and deteriorated cell injury. These effects were inhibited by ICG-001. Stromal cell-derived factor (SDF)-1α, the ligand of CXCR4, stimulated the activation of JAK2/STAT3 and JAK3/STAT6 signalling in HKC-8 cells. Overexpression of STAT3 or STAT6 decreased the abundance of GSK3β mRNA. Silencing of STAT3 or STAT6 significantly blocked SDF-1α-induced activation of β-catenin and fibrotic lesions. These results uncover a novel mechanistic linkage between CXCR4 and β-catenin activation in renal fibrosis in association with JAK/STAT/GSK3β pathway. Our studies also suggest that targeted inhibition of CXCR4 may provide better therapeutic effects on renal fibrosis by inhibiting multiple downstream signalling cascades.

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C-X-C Motif Chemokine Receptor 4 Blockade Promotes Tissue Repair After Myocardial Infarction by Enhancing Regulatory T Cell Mobilization and Immune-Regulatory Function

Abstract: Supplemental Digital Content is available in the text.

Cited by 95 publications

References 51 publications

Angiotensin-(1-7) oral treatment after experimental myocardial infarction leads to downregulation of CXCR4

Angiotensin-(1-7) oral treatment after experimental myocardial infarction leads to downregulation of CXCR4

Myocardial infarction triggers cardioprotective antigen-specific T helper cell responses

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

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