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- W4313125615 abstract "Coronary artery calcium (CAC) is a hallmark of coronary artery disease (CAD) with increased CAC levels associated with increased risk for CAD related morbidity and mortality. The development of CAC is a pathological process driven by the modulation of smooth muscle cells (SMCs) and maladaptive extracellular matrix remodeling. In the most recent multi-ancestry meta-analysis of more than 35,000 individuals, FHL5 (Four-and-a-half LIM domains 5) was prioritized as a novel CAC gene through Bayesian colocalization and epigenomic analyses. scRNA-seq studies of human coronary and carotid arteries revealed high enrichment of FHL5 gene expression in SMC and pericyte populations. These preliminary studies motivate our hypothesis that FHL5 functions as a transcriptional regulator of vascular remodeling pathways associated with increased CAC risk. Following treatment of SMCs with a calcifying cocktail, stable FHL5 overexpression promoted the osteogenic SMC phenotypic transition, characterized by increased levels of osteogenic activators and reduced expression of SMC contractile markers. This osteogenic gene signature correlated with increased SMC calcification, consistent with the direction of effect of the CAC risk allele. To provide insights into the transcriptional program regulated by FHL5 that contributes to the vascular calcification phenotype, we mapped FHL5 binding sites in SMCs using the CUT&RUN method. We identified 17,201 FHL5 binding sites that overlapped the active enhancer mark H3K27ac. FHL5 target genes were enriched in pathways linked to vascular remodeling, such as cell adhesion and extracellular matrix organization. Moreover, risk variants for pulse pressure, a metric of arterial stiffness that is highly correlated with CAC, was enriched in FHL5 binding sites. Lastly, integration with FHL5 trans-eQTL target genes in STARNET arterial tissues revealed a network of CAD-associated candidate genes regulated by FHL5 in vitro and in vivo that impact SMC proliferation, migration, and calcification. Taken together, we provide evidence that FHL5 regulates a network of genes linked to arterial stiffness, which may explain the underlying mechanism of its genetic association with CAC in individuals from the general population." @default.
- W4313125615 created "2023-01-06" @default.
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- W4313125615 date "2022-05-01" @default.
- W4313125615 modified "2023-10-18" @default.
- W4313125615 title "Abstract 466: Fhl5 Enhances Vascular Calcification By Regulating Smooth Muscle Cell Transcriptional Networks" @default.
- W4313125615 doi "https://doi.org/10.1161/atvb.42.suppl_1.466" @default.
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