Foam Cell-Derived CXCL14 Muti-Functionally Promotes Atherogenesis and Is a Potent Therapeutic Target in Atherosclerosis

Tong, Weilin; Duan, Yaqi; Yang, Rumeng; Wang, Ying; Peng, Changqing; Huo, Zitian; Wang, Guoping

doi:10.1007/s12265-019-09915-z

Cited by 8 publications

(11 citation statements)

References 22 publications

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“…Cytokine CXCL14 was the top IGF-1 downregulated gene in MF-high spots (Table 3). CXCL14 was upregulated in MF-derived foam cells and CXCL14 peptide-induced immunotherapy suppressed atherosclerosis in Apoe -/- mice 46 suggesting a pro-atherogenic role of CXCL14.…”

Section: Resultsmentioning

confidence: 96%

“…In vitro and in vivo studies have implicated AP-1 as a critical common inflammatory transcription factor mediating progression of atherogenesis 68 and have suggested that AP-1 inhibition is a promising strategy to treat atherosclerosis 69 . AP-1 was reported to mediate oxidized lipid-induced CXCL14 upregulation in MF-derived foam cells 46 . Here we report that IGF-1-induced FOS/FOSB downregulation correlated with CXCL14 gene expression decrease in MF-high spots.…”

Section: Discussionmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted September 26, 2022. ; https://doi.org/10.1101/2022.09.23.509213 doi: bioRxiv preprint derived foam cells and CXCL14 peptide-induced immunotherapy suppressed atherosclerosis in Apoe -/mice 46 suggesting a pro-atherogenic role of CXCL14.…”

Section: Igf-1 Changes the Global Transcriptomic Profile Of Coronary ...mentioning

confidence: 99%

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Insulin-Like Growth Factor I Reduces Coronary Atherosclerosis in Pigs With Familial Hypercholesterolemia

Sukhanov

Higashi

Yoshida

et al. 2022

Preprint

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ObjectiveAlthough murine models of coronary atherosclerotic disease (CAD) have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We tested IGF-1 effects in atherosclerotic FH pigs to consider use of IGF-1 to treat CAD in humans. FH pigs were administered with IGF-1 for 6 months. Atherosclerosis was quantified by serial intravascular ultrasound (IVUS) and histology, plaque composition - by immunohistochemistry. We used spatial transcriptomics (ST) analysis to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects.ResultsIGF-1-injected FH pigs had 1.8-fold increase in total circulating IGF-1 levels compared to control. IGF-1 decreased relative coronary atheroma (IVUS) and lesion cross-sectional area (histology). IGF-1 induced vascular hypertrophy and reduced circulating triglycerides, markers of systemic oxidative stress and pro-atherogenic CXCL12 chemokine levels. IGF-1 increased fibrous cap thickness, and reduced necrotic core size, macrophage content, and cell apoptosis, changes consistent with promotion of a stable plaque phenotype. IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1’s effect on atherosclerosis.ConclusionsIGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials. ST profiling of plaques provided novel insights into potential mechanisms.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Igf-1 Changes the Global Transcriptomic Profile Of Coronary ...mentioning

confidence: 99%

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Insulin-Like Growth Factor I Reduces Coronary Atherosclerosis in Pigs With Familial Hypercholesterolemia

Sukhanov

Higashi

Yoshida

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Cytokine CXCL14 was the top IGF-1–downregulated gene in MF-high spots ( Table 3 ). CXCL14 was upregulated in MF-derived foam cells, and CXCL14 peptide-induced immunotherapy suppresses atherosclerosis in Apoe –/– mice ( 50 ), suggesting a proatherogenic role of CXCL14.…”

Section: Resultsmentioning

confidence: 99%

“…In vitro and in vivo studies have implicated AP-1 as a critical common inflammatory transcription factor mediating progression of atherogenesis ( 73 ) and have suggested that AP-1 inhibition is a promising strategy to treat atherosclerosis ( 74 ). AP-1 was reported to mediate oxidized lipid-induced CXCL14 upregulation in MF-derived foam cells ( 50 ). Here we report that IGF-1–induced FOS/FOSB downregulation correlated with CXCL14 gene expression decrease in MF-high spots.…”

Section: Discussionmentioning

confidence: 99%

Insulin-like growth factor 1 reduces coronary atherosclerosis in pigs with familial hypercholesterolemia

et al. 2023

View full text Add to dashboard Cite

Although murine models of coronary atherosclerotic disease have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We administered human recombinant IGF-1 or saline (control) in atherosclerotic FH pigs for 6 months. IGF-1 decreased relative coronary atheroma in vivo (intravascular ultrasound) and reduced lesion cross-sectional area (postmortem histology). IGF-1 increased plaque's fibrous cap thickness, and reduced necrotic core, macrophage content, and cell apoptosis consistent with promotion of a stable plaque phenotype. IGF-1 reduced circulating triglycerides, markers of systemic oxidative stress and CXCL12 chemokine levels. We used spatial transcriptomics (ST) to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects. ST analysis shows that IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1's effect on atherosclerosis. Thus, IGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials.

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Lnc_000048 Promotes Histone H3K4 Methylation of MAP2K2 to Reduce Plaque Stability by Recruiting KDM1A in Carotid Atherosclerosis

et al. 2023

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Stabilizing and inhibiting plaque formation is a key challenge for preventing and treating ischemic stroke. KDM1A-mediated histone modifications, which involved in the development of training immunity, ultimately exacerbate the outcomes of inflammation. Although lncRNAs can recruit KDM1A to participate in histone methylation modification and regulate inflammation, cell proliferation, and other biological processes, little is known about the role of KDM1A-lncRNA interaction during atherosclerosis. The present study sought to delineate the effect of the interaction between lnc_000048 and KDM1A on plaque rupture in carotid atherosclerosis, as well as the potential mechanism. Our results revealed that lnc_000048 reduced the activity of histone demethylase and activated MAP2K2 expression by interacting with KDM1A. Furthermore, upregulated lnc_000048 indirectly regulated ERK phosphorylation by MAP2K2 and eventually activated the inflammatory response through the MAPK pathway, which was involved in atherosclerosis. Importantly, our study using ApoE-/- mice confirmed the regulatory role of lnc_000048 in promoting inflammation and collagen degradation in atherosclerotic plaques. These results suggest that targeting the lnc_000048 /KDM1A/MAP2K2/ERK axis may be a promising strategy for preventing atherosclerosis.

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Foam Cell-Derived CXCL14 Muti-Functionally Promotes Atherogenesis and Is a Potent Therapeutic Target in Atherosclerosis

Cited by 8 publications

References 22 publications

Insulin-Like Growth Factor I Reduces Coronary Atherosclerosis in Pigs With Familial Hypercholesterolemia

Insulin-Like Growth Factor I Reduces Coronary Atherosclerosis in Pigs With Familial Hypercholesterolemia

Insulin-like growth factor 1 reduces coronary atherosclerosis in pigs with familial hypercholesterolemia

Lnc_000048 Promotes Histone H3K4 Methylation of MAP2K2 to Reduce Plaque Stability by Recruiting KDM1A in Carotid Atherosclerosis

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