Biology subjects

Reinberger, T.

Publications and source records attributed to Reinberger, T..

3 recordsLinked to original sources

bioRxiv2025

Epitranscriptomic landscape of vascular smooth muscle cell phenotypic transitions highlights uridine RNA modifications associated with post-transcriptional regulation

BackgroundVascular smooth muscle cells (VSMCs) phenotypic plasticity can modulate atherosclerosis progression. Although several gene regulatory steps towards pro-inflammatory phenotypes have been well-studied, epitranscriptomic changes during this transition and their regulatory roles remain unexplored. Methods and ResultsPrimary human VSMCs stimulated with TGF-{beta}1 to induce atheroprotective, contractile, and matrix-producing state and with IL1-{beta} plus PDGF-BB to induce a highly energetic, pro-inflammatory state, confirmed by Illumina bulk RNA sequencing and proteomics. Untargeted screening of mRNA base modifications using Oxford Nanopore Technologies direct RNA sequencing and xPore analysis revealed enhanced uridine modification within a GUUUU motif in pro-inflammatory VSMCs. Modified uridines were enriched in 3-UTR and accessible RNA structures, with implications on Poly(A) tail dynamics and miRNA binding. ConclusionsAtheroprotective and pro-atherogenic treatments induce distinct epitranscriptomic landscapes composed of different modification types, often co-localized in the transcript. Modified uridines in mRNAs are abundant in a high-energy, pro-inflammatory VSMC state and associated with post-transcriptional regulation. n summary, epitranscriptomics adds a novel regulatory layer to VSMC phenotypic transitions critical for atherosclerosis development and progression. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/694735v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@933071org.highwire.dtl.DTLVardef@151564borg.highwire.dtl.DTLVardef@f862e9org.highwire.dtl.DTLVardef@125c509_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic AbstractC_FLOATNO C_FIG

molecular biology↗

bioRxiv2023

Female gene networks are expressed in myofibroblast-like smooth muscle cells in vulnerable atherosclerotic plaques.

Women presenting with coronary artery disease (CAD) more often present with fibrous atherosclerotic plaques, which are currently understudied. Phenotypically modulated smooth muscle cells (SMCs) contribute to atherosclerosis in women. How these phenotypically modulated SMCs shape female versus male plaques is unknown. Here, we show sex-stratified gene regulatory networks (GRNs) from human carotid atherosclerotic tissue. Prioritization of these networks identified two main SMC GRNs in late-stage atherosclerosis. Single-cell RNA-sequencing mapped these GRNs to two SMC phenotypes: a phenotypically modulated myofibroblast-like SMC network and a contractile SMC network. The myofibroblast-like GRN was mostly expressed in plaques that were vulnerable in females. Finally, mice orthologs of the female myofibroblast-like genes showed retained expression in advanced plaques from female mice but were downregulated in male mice during atherosclerosis progression. Female atherosclerosis is driven by GRNs that promote a fibrous vulnerable plaque rich in myofibroblast-like SMCs.

bioinformatics↗

bioRxiv2021

Deficiency of ZC3HC1 increases vascular smooth muscle cell migration, proliferation and neointima formation following injury

RationaleThe ZC3HC1 gene has been linked to various cardiovascular traits. One variant, rs11556924-T, has been found to lower the risk of coronary artery disease (CAD) and blood pressure but increases carotid intima-media thickness (IMT). ObjectiveThis study aimed to determine how ZC3HC1 affects IMT using in vitro and in vivo models. We analyzed the effect of the rs11556924-T allele on ZC3HC1 expression in vascular smooth muscle cells (SMCs) from 151 multi-ethnic heart transplant donors. The results showed that rs11556924-T was associated with lower ZC3HC1 expression and faster SMC migration. ZC3HC1 knockdown (KD) experiments supported these findings, showing increased migration and proliferation. Mechanistically ZC3HC1 KD led to decreased expression of contractile marker genes and the accumulation of cyclin B1, a key cell cycle protein. Pathway analysis of differentially expressed genes between ZC3HC1 KD and controls SMCs showed decreased expression of genes in the cell division and cytoskeleton organization pathways, as well as higher expression of genes involved in extracellular matrix organization and cytokine-mediated signaling. To validate these findings in vivo, we generated and characterized knockout (Zc3hc1-/-) mice. These mice had enhanced neointima formation in response to arterial injury and faster SMCs migration ability. However, complete loss of Zc3hc1 led to a significant reduction in SMC proliferation and lower cyclin B1 protein level. In addition, immunostaining and confocal microscopy demonstrated, for the first time, that ZC3HC1 and Cyclin B1 were located at the cleavage furrow during mitotic progression of SMCs. ConclusionsCollectively, our study suggests that lower ZC3HC1/NIPA level leads to increased SMC migration and neointima formation. Moreover, we proposed a biphasic role of NIPA in proliferation. Lower levels of NIPA promote SMC proliferation, while complete loss of NIPA hampers cell division and abrogates proliferation.

genetics↗