Targeting Epsins to Inhibit Fibroblast Growth Factor Signaling While Potentiating Transforming Growth Factor-β Signaling Constrains Endothelial-to-Mesenchymal Transition in Atherosclerosis.

Abstract

BACKGROUND:

Epsin endocytic adaptor proteins are implicated in the progression of atherosclerosis; however, the underlying molecular mechanisms have not yet been fully defined. In this study, we determined how epsins enhance endothelial-to-mesenchymal transition (EndoMT) in atherosclerosis and assessed the efficacy of a therapeutic peptide in a preclinical model of this disease.

METHODS:

Using single-cell RNA sequencing combined with molecular, cellular, and biochemical analyses, we investigated the role of epsins in stimulating EndoMT using knockout in Apoe-/- and lineage tracing/proprotein convertase subtilisin/kexin type 9 serine protease mutant viral-induced atherosclerotic mouse models. The therapeutic efficacy of a synthetic peptide targeting atherosclerotic plaques was then assessed in Apoe-/- mice.

RESULTS:

Single-cell RNA sequencing and lineage tracing revealed that epsins 1 and 2 promote EndoMT and that the loss of endothelial epsins inhibits EndoMT marker expression and transforming growth factor-β signaling in vitro and in atherosclerotic mice, which is associated with smaller lesions in the Apoe-/- mouse model. Mechanistically, the loss of endothelial cell epsins results in increased fibroblast growth factor receptor-1 expression, which inhibits transforming growth factor-β signaling and EndoMT. Epsins directly bind ubiquitinated fibroblast growth factor receptor-1 through their ubiquitin-interacting motif, which results in endocytosis and degradation of this receptor complex. Consequently, administration of a synthetic ubiquitin-interacting motif-containing peptide atheroma ubiquitin-interacting motif peptide inhibitor significantly attenuates EndoMT and progression of atherosclerosis.

CONCLUSIONS:

We conclude that epsins potentiate EndoMT during atherogenesis by increasing transforming growth factor-β signaling through fibroblast growth factor receptor-1 internalization and degradation. Inhibition of EndoMT by reducing epsin-fibroblast growth factor receptor-1 interaction with a therapeutic peptide may represent a novel treatment strategy for atherosclerosis.

• Authors: Yunzhou Dong, Beibei Wang, Mulong Du, Bo Zhu, Kui Cui, Kathryn Li, Ke Yuan, Douglas B Cowan, Sudarshan Bhattacharjee, Scott Wong, Jinjun Shi, Da-Zhi Wang, Kaifu Chen, Joyce Bischoff, MacRae F Linton, Hong Chen
• Journal: Circulation (Circulation) Vol. 147 Issue 8 Pg. 669-685 (02 21 2023) ISSN: 1524-4539 [Electronic] United States
• PMID: 36591786 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• epsin
• Transforming Growth Factor beta
• Fibroblast Growth Factors
• Apolipoproteins E
• Receptors, Fibroblast Growth Factor
• Transforming Growth Factors
• Ubiquitins

Topics

• Mice
• Animals
• Transforming Growth Factor beta
• Fibroblast Growth Factors
• Apolipoproteins E
• Atherosclerosis (genetics)
• Receptors, Fibroblast Growth Factor
• Transforming Growth Factors
• Ubiquitins