Epigenetic Induction of Smooth Muscle Cell Phenotypic Alterations in Aortic Aneurysms and Dissections

Authors

Abhijit Chakraborty
Yanming Li
Chen Zhang
Yang Li
Kimberly R Rebello
Shengyu Li
Samantha Xu
Hernan G Vasquez
Lin Zhang
Wei Luo
Guangyu Wang
Kaifu Chen
Joseph S Coselli
Scott A LeMaire
Ying H Shen

Language

English

Publication Date

9-19-2023

Journal

Circulation

DOI

10.1161/CIRCULATIONAHA.123.063332

PMID

37555319

PMCID

PMC10529114

PubMedCentral® Posted Date

9-19-2024

PubMedCentral® Full Text Version

Author MSS

Abstract

BACKGROUND: Smooth muscle cell (SMC) phenotypic switching has been increasingly detected in aortic aneurysm and dissection (AAD) tissues. However, the diverse SMC phenotypes in AAD tissues and the mechanisms driving SMC phenotypic alterations remain to be identified.

METHODS: We examined the transcriptomic and epigenomic dynamics of aortic SMC phenotypic changes in mice with angiotensin II-induced AAD by using single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin. SMC phenotypic alteration in aortas from patients with ascending thoracic AAD was examined by using single-cell RNA sequencing analysis.

RESULTS: Single-cell RNA sequencing analysis revealed that aortic stress induced the transition of SMCs from a primary contractile phenotype to proliferative, extracellular matrix-producing, and inflammatory phenotypes. Lineage tracing showed the complete transformation of SMCs to fibroblasts and macrophages. Single-cell sequencing assay for transposase-accessible chromatin analysis indicated that these phenotypic alterations were controlled by chromatin remodeling marked by the reduced chromatin accessibility of contractile genes and the induced chromatin accessibility of genes involved in proliferation, extracellular matrix, and inflammation. IRF3 (interferon regulatory factor 3), a proinflammatory transcription factor activated by cytosolic DNA, was identified as a key driver of the transition of aortic SMCs from a contractile phenotype to an inflammatory phenotype. In cultured SMCs, cytosolic DNA signaled through its sensor STING (stimulator of interferon genes)-TBK1 (tank-binding kinase 1) to activate IRF3, which bound and recruited EZH2 (enhancer of zeste homolog 2) to contractile genes to induce repressive H3K27me3 modification and gene suppression. In contrast, double-stranded DNA-STING-IRF3 signaling induced inflammatory gene expression in SMCs. In

CONCLUSIONS: Our study reveals the dynamic epigenetic induction of SMC phenotypic alterations in AAD. DNA damage and cytosolic leakage drive SMCs from a contractile phenotype to an inflammatory phenotype.

Keywords

Humans, Mice, Animals, Epigenomics, Aortic Aneurysm, Phenotype, Aortic Aneurysm, Thoracic, Aortic Dissection, Myocytes, Smooth Muscle, DNA, Chromatin, Epigenesis, Genetic, Cells, Cultured, aortic aneurysm, aortic dissection, smooth muscle cell, phenotypic switching, STING, IRF3

Published Open-Access

yes

Recommended Citation

Chakraborty, Abhijit; Li, Yanming; Zhang, Chen; et al., "Epigenetic Induction of Smooth Muscle Cell Phenotypic Alterations in Aortic Aneurysms and Dissections" (2023). Faculty and Staff Publications. 3702.
https://digitalcommons.library.tmc.edu/baylor_docs/3702