Epigenetic dysregulation in cardiovascular aging and disease

Allison B Herman,James R Occean,Payel Sen

doi:10.20517/jca.2021.16

Abstract

Cardiovascular disease (CVD) is the leading cause of mortality and morbidity for all sexes, racial and ethnic groups. Age, and its associated physiological and pathological consequences, exacerbate CVD incidence and progression, while modulation of biological age with interventions track with cardiovascular health. Despite the strong link between aging and CVD, surprisingly few studies have directly investigated heart failure and vascular dysfunction in aged models and subjects. Nevertheless, strong correlations have been found between heart disease, atherosclerosis, hypertension, fibrosis, and regeneration efficiency with senescent cell burden and its proinflammatory sequelae. In agreement, senotherapeutics have had success in reducing the detrimental effects in experimental models of cardiovascular aging and disease. Aside from senotherapeutics, cellular reprogramming strategies targeting epigenetic enzymes remain an unexplored yet viable option for reversing or delaying CVD. Epigenetic alterations comprising local and global changes in DNA and histone modifications, transcription factor binding, disorganization of the nuclear lamina, and misfolding of the genome are hallmarks of aging. Limited studies in the aging cardiovascular system of murine models or human patient samples have identified strong correlations between the epigenome, age, and senescence. Here, we compile the findings in published studies linking epigenetic changes to CVD and identify clear themes of epigenetic deregulation during aging. Pending direct investigation of these general mechanisms in aged tissues, this review predicts that future work will establish epigenetic rejuvenation as a potent method to delay CVD.

Highlights

Cardiovascular disease (CVD), including heart failure, hypertension, atherosclerosis, and cardiomyopathy, remains the leading cause of death worldwide and carries a severe socioeconomic burden
While studies have outlined that accumulated damage to mitochondria, proteins, and DNA with age contributes to cardiomyocyte malfunction, telomere damage and cellular senescence are critical to heart failure in humans, and more efforts will be needed to fully elucidate the contribution of senescent cardiomyocytes to age-related cardiac pathologies[47]
We propose that investigation of these distinct DNA modifications in cardiac aging and disease is an understudied but important future research direction

Summary

Introduction

Cardiovascular disease (CVD), including heart failure, hypertension, atherosclerosis, and cardiomyopathy, remains the leading cause of death worldwide and carries a severe socioeconomic burden. Senescent cells have been implicated in several CVD pathologies, most notably, atherosclerosis[28], AAA[29], cardiac fibrosis[30], heart failure[31], and hypertension[32]. While studies have outlined that accumulated damage to mitochondria, proteins, and DNA with age contributes to cardiomyocyte malfunction, telomere damage and cellular senescence are critical to heart failure in humans, and more efforts will be needed to fully elucidate the contribution of senescent cardiomyocytes to age-related cardiac pathologies[47].

Results

Conclusion