Diabetes and Its Cardiovascular Complications: Potential Role of the Acetyltransferase p300

Abstract

Diabetes has been shown to accelerate vascular senescence, which is associated with chronic inflammation and oxidative stress, both implicated in the development of endothelial dysfunction. This condition represents the initial alteration linking diabetes to related cardiovascular (CV) complications. Recently, it has been hypothesised that the acetyltransferase, p300, may contribute to establishing an early vascular senescent phenotype, playing a relevant role in diabetes-associated inflammation and oxidative stress, which drive endothelial dysfunction. Specifically, p300 can modulate vascular inflammation through epigenetic mechanisms and transcription factors acetylation. Indeed, it regulates the inflammatory pathway by interacting with nuclear factor kappa-light-chain-enhancer of activated B cells p65 subunit (NF-κB p65) or by inducing its acetylation, suggesting a crucial role of p300 as a bridge between NF-κB p65 and the transcriptional machinery. Additionally, p300-mediated epigenetic modifications could be upstream of the activation of inflammatory cytokines, and they may induce oxidative stress by affecting the production of reactive oxygen species (ROS). Because several in vitro and in vivo studies shed light on the potential use of acetyltransferase inhibitors, a better understanding of the mechanisms underlying the role of p300 in diabetic vascular dysfunction could help in finding new strategies for the clinical management of CV diseases related to diabetes.

Keywords: cardiovascular disease; diabetes; endothelial dysfunction; epigenetics; inflammation; oxidative stress; p300; senescence.

Figure 1

Endothelial cell senescence: Senescence is triggered by various stimuli, including changes in telomeric structure, oxidative stress, mitochondrial dysfunction, inflammation and DNA damage, which contribute to cell cycle arrest through the activation of the p53/p21CIP1 or p16INK4A/hosphor-Rb tumour suppressor pathways. In addition, senescent cells exhibit activation of the senescence-associated secretory phenotype (SASP) characterised by the increased lysosomal activity and accumulation of β-galactosidase. The SASP leads to the upregulation and release of growth factors, cytokines and proteases that can exert detrimental effects.

Figure 2

p300 mechanisms underlying vascular inflammation and oxidative stress and the role of some HAT inhibitors.