Acetyl-lysine erasers and readers in the control of pulmonary hypertension and right ventricular hypertrophy

Abstract

Acetylation of lysine residues within nucleosomal histone tails provides a crucial mechanism for epigenetic control of gene expression. Acetyl groups are coupled to lysine residues by histone acetyltransferases (HATs) and removed by histone deacetylases (HDACs), which are also commonly referred to as "writers" and "erasers", respectively. In addition to altering the electrostatic properties of histones, lysine acetylation often creates docking sites for bromodomain-containing "reader" proteins. This review focuses on epigenetic control of pulmonary hypertension (PH) and associated right ventricular (RV) cardiac hypertrophy and failure. Effects of small molecule HDAC inhibitors in pre-clinical models of PH are highlighted. Furthermore, we describe the recently discovered role of bromodomain and extraterminal (BET) reader proteins in the control of cardiac hypertrophy, and provide evidence suggesting that one member of this family, BRD4, contributes to the pathogenesis of RV failure. Together, the data suggest intriguing potential for pharmacological epigenetic therapies for the treatment of PH and right-sided heart failure.

Keywords: HDAC; RV hypertrophy; bromodomain; bromodomaine; epigenetics; hypertension pulmonaire; hypertrophie ventriculaire droite; pulmonary hypertension; épigénétique.

Fig. 1

Regulation of histone acetylation. (A) Lysine residues within nucelosomal histone tails are acetylated by histone acetyltransferases (HATs) and deacetylated by histone deacetylases (HDACs), which are referred to as writers and erasers, respectively. Acetylation creates docking sites for bromodomain and extraterminal (BET) reader proteins. (B) HDACs fall into four classes. Class II is further subdivided into class IIa and class IIb HDACs. All of the zinc-dependent HDACs are depicted.

Fig. 2

Efficacy of HDAC inhibitors in models of PH and RV hypertrophy. Pan- and class I HDAC inhibitors have been tested in a variety of rodent models of PH and RV hypertrophy. With two exceptions (TSA in the rat pulmonary artery banding [PAB] model and TSA in the rat SU5416 plus hypoxia [SU-Hx] model), HDAC inhibitors lowered pulmonary arterial pressure and exerted beneficial effects in the heart. References are indicated.

Fig. 3

BET acetyl-lysine binding proteins. (A) BRD2, BRD3, BRD4, and testis-specific BRDT comprise the bromodomain and extraterminal (BET) family of proteins. BET proteins contain conserved N-terminal acetyl lysine binding bromodomains (BD1 and BD2) and an extraterminal domain (ET). BRD4 and BRDT are able to interact with the positive transcription elongation factor b (P-TEFb complex) via a carboxyl-terminal motif (CTM). (B) BRD4 bromodomains read histone acetylation marks in gene regulatory elements. Through the CTM:P-TEFb association, BRD4 directs CDK9-mediated phosphorylation of RNA Pol II, resulting in transcriptional elongation. JQ1 is an acetyl-lysine mimetic that blocks binding of BRD4 to acetylated histones.

Fig. 4

BRD4 protein expression is induced during RV hypertrophy. Male Sprague Dawley rats were given a dose of the VEGF receptor inhibitor SU5416 and housed for three weeks in a hypobaric chamber simulating an altitude of 18 000 feet above sea level and a 10% O2 environment; these rats are referred to as SU-Hx rats. Rats were subsequently placed at Denver altitude for an additional month. Control rats (Normoxia) were housed in “sea level” chambers for four weeks followed by Denver altitude for four weeks. SU-Hx rats had significant RV hypertrophy, as evidenced by a ~2-fold increase in RV/LV + septum ratio (A). RV hypertrophy coincided with a dramatic increase in levels of BRD4 protein in the RV (B).