P300/CBP Associated Factor Regulates Nitroglycerin-Dependent Arterial Relaxation by N ^ε -Lysine Acetylation of Contractile Proteins

Abstract

Objective-To address the role of epigenetic enzymes in the process of arterial vasorelaxation and nitrate tolerance, in vitro and in vivo experiments were performed in the presence or absence of glyceryl trinitrate (GTN) or histone deacetylases/ histone acetylases modulators. Methods and Results-In vitro single GTN administration rapidly increased cGMP synthesis and protein N ε -lysine acetylation in rat smooth muscle cells, including myosin light chain and smooth muscle actin. This phenomenon determined a decrease in myosin light chain phosphorylation and actomyosin formation. These effects were abolished by prolonged exposure to GTN and rescued by treatment with trichostatin A. In vivo, adult male rats were treated for 72 hours with subcutaneous injections of GTN alone or in combination with the histone deacetylases inhibitors trichostatin A, suberoylanilide hydroxamic acid, MS-27-275, or valproic acid. Ex vivo experiments performed on aortic rings showed that the effect of tolerance was reversed by all proacetylation drugs, including the p300/CREB binding protein-associated factor activator pentadecylidenemalonate 1b (SPV106). Any response to GTN was abolished by anacardic acid, a potent histone acetylases inhibitor. Conclusion-This

The Histone Acetylase Activator Pentadecylidenemalonate 1b Rescues Proliferation and Differentiation in the Human Cardiac Mesenchymal Cells of Type 2 Diabetic Patients

“…Prior observations indicated that the HAT activator SPV106 was proficient at promoting histone acetylation in normal and physiopathological conditions (23,28,29). In this study, we wished to investigate whether D-CMSC could be sensitive to the increase of histone acetylation levels.…”

A Nitric Oxide-dependent Cross-talk between Class I and III Histone Deacetylases Accelerates Skin Repair

“…Specifically, the silencing of polycomb or the activation of HDACs and SIRTs have been reported during the various phases of skin repair but their role in the regulation of these processes is yet poorly characterized (25,26). Intriguingly, NO has been found functionally relevant in all phases of WH and recent observations have shown that it modulates gene expression by regulating the function of epigenetic enzymes such as histone acetylases and deacetylases (4,27). Noteworthy, members of the class-III HDACs, the sirtuins, have been described to modulate eNOS function eliciting a significant increase in NO production by a lysine deacetylation-dependent process (8).…”

More answers to the still unresolved question of nitrate tolerance

“…drugs that act on the acetylation levels of histones, thereby modifying DNA expression), prevent tolerance in a murine model. 18 The possible clinical applications of this observation remain to be explored.…”

“…by modulating the processes, for instance histone acetylation and deacetylation, which control which and how much genes are expressed). 18 Although research on the role of epigenetic regulation in cardiovascular pathophysiology is at its very beginning, it has been shown that the so-called 'epi-drugs' (i.e. drugs that act on the acetylation levels of histones, thereby modifying DNA expression), prevent tolerance in a murine model.…”