ABSTRACT
BACKGROUND: Heart failure is typical in the elderly. Metabolic remodeling of cardiomyocytes underlies inexorable deterioration of cardiac function with aging: glycolysis increases at the expense of oxidative phosphorylation, causing an energy deficit contributing to impaired contractility. Better understanding of the mechanisms of this metabolic switching could be critical for reversing the condition. METHODS: To investigate the role of 3 histone modifications (H3K27ac, H3K27me3, and H3K4me1) in the metabolic remodeling occurring in the aging heart, we cross-compared epigenomic, transcriptomic, and metabolomic data from mice of different ages. In addition, the role of the transcriptional coactivator p300 (E1A-associated binding protein p300)/CBP (CREB binding protein) in cardiac aging was investigated using a specific inhibitor of this histone acetyltransferase enzyme. RESULTS: We report a set of species-conserved enhancers associated with transcriptional changes underlying age-related metabolic remodeling in cardiomyocytes. Activation of the enhancer region of Hk2-a key glycolysis pathway gene-was fostered in old age-onset mouse heart by pseudohypoxia, wherein hypoxia-related genes are expressed under normal O2 levels, via increased activity of P300/CBP. Pharmacological inhibition of this transcriptional coactivator before the onset of cardiac aging led to a more aerobic, less glycolytic, metabolic state, improved heart contractility, and overall blunting of cardiac decline. CONCLUSIONS: Taken together, our results suggest how epigenetic dysregulation of glycolysis pathway enhancers could potentially be targeted to treat heart failure in the elderly.
Subject(s)
Heart Failure , Transcription Factors , Humans , Mice , Animals , Aged , Histone Acetyltransferases , Regulatory Sequences, Nucleic Acid , Transcriptome , Transcriptional ActivationABSTRACT
Due to their different biological functions, extracellular vesicles (EVs) have great potential from a therapeutic point of view. They are released by all cell types, carrying and delivering different kinds of biologically functional cargo. Under pathological events, cells can increase their secretion of EVs and can release different amounts of cargo, thus making EVs great biomarkers as indicators of pathological progression. Moreover, EVs are also known to be able to transport and deliver cargo to different recipient cells, having an important role in cellular communication. Interestingly, EVs have recently been explored as biological alternatives for the delivery of therapeutics, being considered natural drug delivery carriers. Because cardiovascular disorders (CVDs) are the leading cause of death worldwide, in this review, we will discuss the up-to-date knowledge regarding the biophysical properties and biological components of EVs, focusing on myocardial infarction, diabetic cardiomyopathy, and sepsis-induced cardiomyopathy, three very different types of CVDs.
ABSTRACT
Cardiovascular disease, the leading cause of death worldwide, has been characterized at the molecular level by alterations in gene expression that contribute to the etiology of the disease. Such alterations have been shown to play a critical role in the development of atherosclerosis, cardiac remodeling, and age-related heart failure. Although much is now known about the cellular and molecular mechanisms in this context, the role of epigenetics in the onset of cardiovascular disease remains unclear. Epigenetics, a complex network of mechanisms that regulate gene expression independently of changes to the DNA sequence, has been highly implicated in the loss of homeostasis and the aberrant activation of a myriad of cellular pathways. More specifically, non-coding RNAs have been gaining much attention as epigenetic regulators of various pathologies. In this review, we will provide an overview of the ncRNAs involved in cell-to-cell communication in cardiovascular disease, namely atherosclerosis, cardiac remodeling, and cardiac ageing, and the potential use of epigenetic drugs as novel therapeutic targets.
