Abstract
Cardiovascular disease is the leading cause of accelerated as well as chronological aging-related human morbidity and mortality worldwide. Genetic, immunologic, unhealthy lifestyles including daily consumption of high-carb/high-fat fast food, lack of exercise, drug addiction, cigarette smoke, alcoholism, and exposure to environmental pollutants like particulate matter (PM)-induced stresses contribute profoundly to accelerated and chronological cardiovascular aging and associated life threatening diseases. All these stressors alter gene expression epigenetically either through activation or repression of gene transcription via alteration of chromatin remodeling enzymes and chromatin landscape by DNA methylation or histone methylation or histone acetylation. Acetyltransferase p300, a major epigenetic writer of acetylation on histones and transcription factors, contributes significantly to modifications of chromatin landscape of genes involved in cellular aging and cardiovascular diseases. In this review, the key findings those implicate acetyltransferase p300 as a major contributor to cellular senescence or aging related cardiovascular pathologies including vascular dysfunction, cardiac hypertrophy, myocardial infarction, cardiac fibrosis, systolic/diastolic dysfunction, and aortic valve calcification are discussed. The efficacy of natural or synthetic small molecule inhibitor targeting acetyltransferase p300 in amelioration of stress-induced dysregulated gene expression, cellular aging, and cardiovascular disease in preclinical study is also discussed.
Highlights
Epigenetics plays a pivotal role in organismal gametogenesis, organogenesis, fetal growth, post-natal growth, adulthood physical/mental maturity, and aging [1]
This study further showed that short hairpin RNAs (shRNA)-mediated depletion of the acetyltransferase p300 inhibits senescence-related gene expression and the cellular senescence process as evidenced by decreased telomere dysfunction-induced foci per cell, significantly less SA-β-Gal positivity, and significantly higher 5-ethynyl-2 -deoxyuridine (EdU) positivity compared to control cells [19]
We demonstrated that doxorubicin induces accelerated cellular senescence or aging processes in three cardiac cell types including cardiomyocytes, cardiac fibroblasts, and vascular endothelial cells as evidenced by elevated levels of senescence regulators p16, p21, p53, Plasminogen activator inhibitor-1 (PAI-1), and senescence marker SA-β-Gal in doxorubicin treated cardiac cells [28]. These results suggest that cardiac cellular senescence contributes to doxorubicin-induced cardiotoxicity and heart failure [25,26,27,28], and acetyltransferase p300 plays a significant role in cardiac cellular aging
Summary
Epigenetics plays a pivotal role in organismal gametogenesis, organogenesis, fetal growth, post-natal growth, adulthood physical/mental maturity, and aging [1]. DNA methylation at CpG site is associated with transcriptional repression and regulated by epigenetic writers like DNA methyltransferases, epigenetic readers such as methyl CpG binding domain protein and transcription factors, and epigenetic eraser like DNA demethylase [3]. Histone acetylation is associated with transcriptional activation and controlled by epigenetic writer histone and factor acetyltransferases like p300, epigenetic readers like brd/bet bromodomain, and epigenetic erasers such as zinc-dependent histone deacetylases or NAD-dependent sirtuins [4,5]. Acetyltransferase p300 plays significant roles in numerous cellular processes including proliferation, migration, differentiation, senescence, and apoptosis through chromatin remodeling in the regulatory regions of genes as an epigenetic regulator and/or an interacting coactivator with specific transcription factors of genes involved in those cellular processes [7,8,9]. The cellular and preclinical studies on the significance of acetyltransferase p300 in cellular aging and cardiovascular disease are discussed
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