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Aging and disease    2020, Vol. 11 Issue (4) : 916-926     DOI: 10.14336/AD.2020.0401
Review |
p300 in Cardiac Development and Accelerated Cardiac Aging
Ghosh Asish K*
Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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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 pressure-induced 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.

Keywords heart development      cardiac aging      epigenetics      acetyltransferase p300      extracellular matrix      air-pollutant      hypertension      hypertrophy      fibrosis      heart failure      epidrugs     
Corresponding Authors: Ghosh Asish K   
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These authors contributed equally to this work.

Just Accepted Date: 17 April 2020   Issue Date: 30 July 2020
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Ghosh Asish K
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Ghosh Asish K. p300 in Cardiac Development and Accelerated Cardiac Aging[J]. Aging and disease, 2020, 11(4): 916-926.
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http://www.aginganddisease.org/EN/10.14336/AD.2020.0401     OR
Figure 1.  Acetyltransferase p300 in cardiac development and accelerated cardiac aging. Physiological level of p300 plays a significant role in heart development: defects in heart development in p300 null mouse embryos and significant percentage of heterozygous mouse embryos. Stresses like hypertension-induced or diabetes-induced or vascular injury-induced elevated level of p300 significantly contributes to accelerated cardiac aging pathologies viz. pathological cardiac hypertrophy, diabetic cardiomyopathy, systolic and diastolic dysfunction, failing hearts with myocardial fibrosis.
Figure 2.  Acetyltransferase p300 (p300), Acetylated histone 3 lysine 9 (AcH3K9) and Type I collagen (fibrosis) are elevated in hypertensive murine hearts. (A) Elevated expression of p300 in Angiotensin II-induced hypertensive murine hearts and its correlation with increased expression of acetylated histone H3 lysine 9 residue (AcH3K9) and elevated levels of ventricular fibrosis. (B) Model depicting the epigenetic regulation of accelerated cardiac aging by deregulated p300 and as a druggable target for accelerated cardiac aging therapy. TF; Transcription factor; MI: myocardial infarction. Inhibitors and modulators of p300 activity used in cell and animal models to suppress the acetyltransferase activity of p300 in hearts and accelerated cardiac aging pathologies: curcumin [24,59,61,63,66]; L002 [22,23]; C646 [22,23]; resveratrol [64,65].
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