Abstract
Hypothesis: VSMC play crucial roles in atherosclerosis via phenotypic switching. The trans-differentiation of VSMC into other cell types might contribute to atherosclerotic lesion development, progression, and the subsequent diseases such as myocardial infarction or stroke. Epsins, a family of endocytic adaptors, are crucial for atherosclerosis development and progression; yet, the role of epsins in VSMC phenotypic modulation is unknown. Methods and Results: To decipher the role of VSMC epsins in regulating atheroma development and progression, we created WT and SMC-specific inducible epsin1/2 double knockout (SMC-iDKO) mice on ApoE -/- background fed a western diet. Using single-cell RNA-seq analysis, we found VSMC and EC population significantly changed in SMC-iDKO/ApoE -/- mice compared to ApoE -/- mice. Using immunofluorescent and FACS analysis, we observed that both VSMC and EC marker genes expressions were up-regulated in DKO-VSMCs indicating that DKO-SMCs were maintaining their SMC phenotype and may further trans-differentiating into ECs via a process called MEndoT, mesenchymal to endothelial transition. Given the critical role of KLF4 in regulating VSMCs phenotype during atheroma progression, we observed diminished KLF4 expression in DKO-SMCs compared to WT treated with oxLDL. Furthermore, we found that epsins interacted with KLF4 with Epsin-UIM domain and their interaction improved KLF4 stability and promoted KLF4 to transfer into nuclei. In this study, we found that epsins were highly expressed and positively correlated with the lesion severity in VSMCs in atherosclerotic. Using immunofluorescent and Oil Red O stainings, we observed reduced lipid accumulation, lesion size and macrophage infiltration but elevated VSMCs in the cap of lesions in SMC-iDKO/ApoE -/- mice compared with ApoE -/- mice. Conclusions: In conclusions, we demonstrated an unexpected role of epsins in regulating phenotypic switching by repressing SM-contractile and EC marker genes expression through an epigenetic regulatory mechanism. Our data suggest that epsins may be a therapeutic target for treating occlusive vascular diseases, and uncover regulatory pathways for therapeutic targeting of SMC transitions in atherosclerotic cardiovascular disease.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
