Recent Advances in Hypertension: Epigenetic Mechanism Involved in Development of Salt-Sensitive Hypertension

Abstract

This review highlights recent insights into the epigenetic mechanism of salt-sensitive hypertension from the fetus to the elderly population, mainly focusing on the DNA methylation and histone modification-mediated regulation of hypertension-associated genes. Maternal malnutrition during pregnancy induces upregulation of angiotensin receptor 1a ( AT1a ) by aberrant DNA methylation, and increased AT1A activity in the hypothalamus develops prenatally programmed salt-sensitive hypertension through renal sympathetic overactivity. In addition, maternal lipopolysaccharide exposure during pregnancy induces upregulation of the Rac1 gene through histone modification by H3K9me2 across generations, resulting in salt-induced activation of the Rac1-MR (mineralocorticoid receptor) pathway in the kidney and the development of salt-sensitive hypertension in F4 and F5 offspring. In mice, aberrant DNA methylation of the Klotho gene, which regulates aging-associated hypertension, decreases the circulating soluble Klotho levels, leading to activation of the vascular Wnt5a-RhoA pathway and vasoconstriction and development of salt-sensitive hypertension because of decreased renal blood flow. A detailed understanding of the environmentally-induced epigenetic modulations related to salt-induced hypertension could be promising for developing preventive and therapeutic approaches to hypertension.

Myosin Light Chain Phosphatase Plays an Important Role in Cardiac Fibrosis in a Model of Mineralocorticoid Receptor‐Associated Hypertension

“…MR‐related hypertension has recently been proposed to be associated with upregulation of Wnt5a‐RhoA/ROCK‐MYPT1 signaling in vascular smooth muscle cells. 18 , 19 However, whether this signaling represents the mechanism mediating cardiac hypertrophy and fibrosis remains unknown. We discovered upregulation of MYPT2 and MLCP activity in cardiomyocytes both in vivo and in vitro after treatment with aldosterone.…”

“…MR‐related hypertension has recently been reported to be associated with the upregulation of ROCK (RhoA/Rho kinase)‐myosin phosphatase target subunit 1 (MYPT1) signaling in arteries. 18 , 19 However, how MYPT signaling affects the heart in MR‐related hypertension remains unknown. A recent study demonstrated that cardiac MLCP plays an important role in cardiac fibrosis as a target of ROCK.…”

Epigenetics of hypertension as a risk factor for the development of coronary artery disease in type 2 diabetes mellitus

“…Epigenetics, which explores the dynamic interplay between genetic factors and the environment, emerges as a critical player in the regulation of blood pressure. Epigenetic changes can be influenced by environmental stimuli such as nutrition, aging, and pharmaceuticals, and importantly, these changes possess the potential for reversibility ( 8 , 9 ). This characteristic sets the stage for a spectrum of treatment possibilities distinct from those for genetic disorders.…”

Vascular Inflammation and Smooth Muscle Contractility: The Role of Nox1-Derived Superoxide and LRRC8 Anion Channels

“…Approximately 50% of the risk for hypertension is inherited 5 and these influences are epigenetically modified by intrauterine and life events. 8,9 Numerous reviews have focused on the critical role of endothelial dysfunction, however, VSMCs also suffer chronic injury. 10 Multiple proinflammatory signaling pathways are hyperactivated including TNF-α (tumor necrosis factor alpha), 11 IL (interleukin)-1β, 12 Ang II (angiotensin II), 13 and growth factors, 14 supporting an inflammatory response that correlates with disease severity.…”