p300 in Cardiac Development and Accelerated Cardiac Aging

Abstract

The heart is the first functional organ that develops during embryonic development. While a heartbeat indicates life, cessation of a heartbeat signals the end of life. Heart disease, due either to congenital defects or to acquired dysfunctions in adulthood, remains the leading cause of death worldwide. Epigenetics plays a key role in both embryonic heart development and heart disease in adults. Stress-induced vascular injury activates pathways involved in pathogenesis of accelerated cardiac aging that includes cellular dysfunction, pathological cardiac hypertrophy, diabetic cardiomyopathy, cardiac matrix remodeling, cardiac dysfunction and heart failure. Acetyltransferase p300 (p300), a major epigenetic regulator, plays a pivotal role in heart development during embryogenesis, as deficiency or abnormal expression of p300 leads to embryonic death at early gestation periods due to deformation of the heart and neural tube. Acetyltransferase p300 controls heart development through histone acetylation-mediated chromatin remodeling and transcriptional regulation of genes required for cardiac development. In adult hearts, p300 is differentially expressed in different chambers and epigenetically controls cardiac gene expression. Deregulation of p300, in response to prohypertrophic and profibrogenic stress signals, is associated with increased recruitment of p300 to several genes including transcription factors, increased acetylation of specific lysines in histones and transcription factors, altered chromatin organization, and increased hypertrophic and fibrogenic gene expression. Cardiac hypertrophy and myocardial fibrogenesis are common pathological manifestations of several stress-induced accelerated cardiac aging-related pathologies, including high blood pressureinduced or environmentally induced cardiac hypertrophy, myocardial infarction, diabetes-induced cardiomyopathy, and heart failure. Numerous studies using cellular and animal models clearly indicate that pharmacologic or genetic normalization of p300 activity has the potential to prevent or halt the progression of cardiac aging pathologies. Based on these preclinical studies, development of safe, non-toxic, small molecule inhibitors/epidrugs targeting p300 is an ideal approach to control accelerated cardiac aging-related deaths worldwide.

Mesenchymal Stem Cell Therapy in Diabetic Cardiomyopathy

“…Histone methylation, acetylation and phosphorylation are also important mechanisms implicated in gene transcription regulation. Increased activity of histone acetyltransferase (HAT) p300 is observed in rat models of DCM and correlates to the severity of cardiac dysfunction, myocardial hypertrophy and fibrosis [ 66 , 67 ]. The influence of histone acetylation on DCM seems to involve the recruitment of transcriptional regulators, since the treatment with an inhibitor of bromodomain-containing protein-4 (BRD4), apabetalone, decreased the risk of major adverse cardiovascular events and the frequency of hospitalizations after recent acute coronary syndrome in DM2 patients [ 68 , 69 ].…”

Inhibition of p300 by Garcinol Protects against Cisplatin-Induced Acute Kidney Injury through Suppression of Oxidative Stress, Inflammation, and Tubular Cell Death in Mice

“…Levels of histone acetylation are modulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Among members of HATs, p300 is involved in various biological processes, including proliferation, differentiation, and apoptosis, through modulating histone acetylation [ 15 , 16 ]. In addition, p300 can directly bind to transcription factors, such as nuclear factor-κB (NF-κB) and p53, and regulate their activities via acetylation [ 17 , 18 , 19 ].…”

Nicotinamide Mononucleotide Alleviates Cardiomyopathy Phenotypes Caused by Short-Chain Enoyl-Coa Hydratase 1 Deficiency

“… 26 , 27 Using H3K4ac-, H3K9ac-, H3K18ac-, H3K27ac-, H4K5ac-, H4K8ac-, H4K12ac-, and H4K16ac-targeting antibodies, we found increased H3K9ac levels, a pathogenic factor in cardiac fibroblasts for fibrosis, in the Echs1 +/- mice heart tissues ( Figure 3B ). 28 Similarly, immunohistochemistry showed increased H3K9ac levels in heart tissues of Echs1 +/- mice compared with that in wild-type mice at week 3 and week 96 ( Figure 2B , Supplemental Figure 3B ). To investigate whether cardiac fibroblasts or cardiomyocytes contributed to the level of alteration of histone 3 acetylation, we assessed the pan-acetylation in both cells from wild-type and Echs1 +/- mice; only primary cardiac fibroblasts from Echs1 +/- mice showed increased pan-acetylation around 20 kDa similar to that in whole-heart tissues ( Figures 3C and 3D ).…”