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.
Highlights
The heart is the first functional organ that develops during embryonic development
The major epigenetic regulators are acetyltransferases, deacetylases, methylases, demethylases, and microRNAs. This minireview only focuses on the significant role of acetyltransferase p300, a major epigenetic regulator, in heart development and stress-induced accelerated cardiac aging associated pathologies
The existence of acetyltransferase p300 was originally discovered in the mid-1980s during the search for adenoviral E1A-interacting cellular proteins involved in adenovirus-controlled mammalian cellular growth [3,4]
Summary
Heart development is a unique and complex process that occurs very early during embryogenesis [1]. Stressinduced accelerated cardiac aging-related pathologies in adults is the leading cause of deaths worldwide. P300 in Heart the major culprits of accelerated cardiac aging related morbidity and mortality. Numerous drugs targeting signaling pathways and synthetic machinery have been developed to reduce the causative factors of heart disease. As epigenetics plays a significant role in cardiovascular disease development, epigenetic regulators are ideal targets for therapy. Very little attention has been paid to developing epidrugs for heart disease. The major epigenetic regulators are acetyltransferases, deacetylases, methylases, demethylases, and microRNAs. The major epigenetic regulators are acetyltransferases, deacetylases, methylases, demethylases, and microRNAs This minireview only focuses on the significant role of acetyltransferase p300, a major epigenetic regulator, in heart development and stress-induced accelerated cardiac aging associated pathologies
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