Bromodomain Blockade for Intimal Hyperplasia — A Good BET?

نویسندگان

  • Allison C. Ostriker
  • Kathleen A. Martin
چکیده

Atherosclerosis contributes to heart attack, stroke, and peripheral hyperplasia by 75% when applied to the vessel prior to angioplasty. vascular disease and remains the leading cause of death in the U.S. (Tabas et al., 2015). Atherosclerotic plaques can be treated by revascularization procedures, including angioplasty, stenting, or bypass surgery, but microtrauma to the blood vessel during these procedures can lead to a complication called intimal hyperplasia, a hyperproliferation of cells in the vascular lumen (Katz et al., 2015). Smooth muscle cells (SMC), which comprise the muscular layer of arteries, retain the remarkable ability to dedifferentiate in response to injury and assume a repair phenotype. These SMC downregulate expression of their characteristic contractile proteins and migrate from the vessel wall into the lumen where they proliferate and secrete matrix proteins, forming a fibrotic scar (Liu et al., 2015). While local drug delivery with drug-eluting stents has been effective in reducing intimal hyperplasia in coronary arteries, intimal hyperplasia remains a major challenge in diabetic patients and in peripheral blood vessels (Katz et al., 2015). In this issue,Wang et al. present exciting findings that targeting epigenetic “reader” proteins is a promising therapeutic strategy for preventing intimal hyperplasia. Our understanding of the smooth muscle phenotypic switching that underlies the intimal hyperplastic response has been largely at the transcriptional level, but recent studies revealed roles for epigenetic regulation, including DNA methylation and modifications of the histone proteins that organizeDNA into chromatin. Collectively, these epigeneticmodifications,made by proteins referred to as “writers” and “erasers”, govern chromatin accessibility to transcription factors (Liu et al. 2015). The bromodomain and extraterminal domain (BET) family of reader proteins serve as critical adaptors, recognizing histone acetylated lysine residues and recruiting additional proteins to promote transcription elongation (Shi and Vakoc, 2014). Wang et al. demonstrate that BET proteins play an important role in intimal hyperplasia. The authors found that the BET protein BRD4 was expressed at low levels in normal rat carotid artery but was highly induced in SMC following balloon angioplasty. BRD4was also present in human vein and artery graft intimal hyperplastic lesions but not in normal vessels. Themost excitingfinding was that a BET-specific bromodomain inhibitor, JQ1, reduced intimal

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عنوان ژورنال:

دوره 2  شماره 

صفحات  -

تاریخ انتشار 2015