Epigenetic regulation in hypertension: mechanistic insights and environmental influences

Hypertension is a leading global cause of cardiovascular, renal, and cerebrovascular morbidity. Beyond classical genetic and environmental determinants, accumulating evidence highlights epigenetic regulation as a key contributor to blood pressure control and vascular pathology. Epigenetic mechanisms, including DNA methylation, histone post-translational modifications, and non-coding RNAs, govern gene expression without altering the underlying DNA sequence, thereby linking environmental and physiological stimuli to stable transcriptional changes. Aberrant epigenetic signatures have been identified in vascular, renal, and endocrine tissues integral to blood pressure regulation, influencing pathways that mediate vascular tone, sodium handling, oxidative stress, and inflammation. Among these, differential methylation and histone modification of renin-angiotensin-aldosterone system (RAAS) genes, including AGT, REN, ACE, and AT1R, have been shown to promote sustained activation of vasoconstrictive and sodium-retentive signaling cascades. Chronic exposure to a high-salt diet (HSD) represents a potent environmental modifier of this epigenetic landscape. Excess dietary sodium can alter CpG methylation patterns, histone acetylation states, and microRNA profiles across multiple tissues, leading to enhanced RAAS activity and vascular dysfunction. These HSD-induced alterations often persist despite subsequent sodium normalization, reflecting an enduring "epigenetic memory" of dietary stress that contributes to salt-sensitive hypertension. Understanding how HSD and other environmental factors reprogram RAAS-related gene networks through epigenetic mechanisms provides critical insight into the molecular basis of hypertension. Moreover, these findings open new avenues for therapeutic intervention utilizing DNA methyltransferase and histone deacetylase inhibitors, as well as RNA-based precision therapies aimed at reversing the maladaptive epigenetic imprint underlying chronic blood pressure elevation.