DOI: 10.1101/509414Jan 4, 2019Paper

The BD2 domain of BRD4 is a determinant in EndoMT and vein graft neointima formation

BioRxiv : the Preprint Server for Biology
Mengxue ZhangLian-Wang Guo

Abstract

Background: Vein-graft bypass is commonly performed to overcome atherosclerosis but is limited by high failure rates, principally due to neointimal wall thickening. Recent studies reveal that endothelial-mesenchymal transition (EndoMT) is critical for vein-graft neointima formation. BETs are a family of Bromo/ExtraTerminal domains-containing epigenetic reader proteins (BRD2, BRD3, BRD4). They bind acetylated histones through their unique tandem bromodomains (BD1, BD2), facilitating transcriptional complex formation and cell-state transitions. The role for BETs, including individual BRDs and their unique BDs, is not well understood in EndoMT and neointimal formation. Methods and Results: Repression of BRD4 expression abrogated TGFbeta1-induced EndoMT, with greater effects than BRD2 or BRD3 knockdown. An inhibitor selective for BD2 in all BETs, but not that for BD1, blocked EndoMT. Moreover, expression of a dominant-negative BRD4-specific BD2 fully abolished EndoMT. Concordantly, BRD4 knockdown repressed TGFbeta1-stimulated increase of ZEB1 protein, a transcription factor integral in EndoMT. In vivo, lentiviral gene transfer of either BRD4 shRNA or dominant negative BRD4-specific BD2 mitigated neointimal development in rat jugula...Continue Reading

Related Concepts

Atherosclerosis
Carotid Arteries
Histones
Gambling, Pathological
Transcription Factor
Transcription, Genetic
Tandem
Internal Jugular Vein Structure
Inhibitors
ZEB1 protein, human

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