The new mechanism of cognitive decline induced by hypertension: High homocysteine-mediated aberrant DNA methylation

Abstract

The prevalence and severity of hypertension-induced cognitive impairment increase with the prolonging of hypertension. The mechanisms of cognitive impairment induced by hypertension primarily include cerebral blood flow perfusion imbalance, white and gray matter injury with blood–brain barrier disruption, neuroinflammation and amyloid-beta deposition, genetic polymorphisms and variants, and instability of blood pressure. High homocysteine (HHcy) is an independent risk factor for hypertension that also increases the risk of developing early cognitive impairment. Homocysteine (Hcy) levels increase in patients with cognitive impairment induced by hypertension. This review summarizes a new mechanism whereby HHcy-mediated aberrant DNA methylation and exacerbate hypertension. It involves changes in Hcy-dependent DNA methylation products, such as methionine adenosyltransferase, DNA methyltransferases, S-adenosylmethionine, S-adenosylhomocysteine, and methylenetetrahydrofolate reductase (MTHFR). The mechanism also involves DNA methylation changes in the genes of hypertension patients, such as brain-derived neurotrophic factor, apolipoprotein E4, and estrogen receptor alpha, which contribute to learning, memory, and attention deficits. Studies have shown that methionine (Met) induces hypertension in mice. Moreover, DNA hypermethylation leads to cognitive behavioral changes alongside oligodendroglial and/or myelin deficits in Met-induced mice. Taken together, these studies demonstrate that DNA methylation regulates cognitive dysfunction in patients with hypertension. A better understanding of the function and mechanism underlying the effect of Hcy-dependent DNA methylation on hypertension-induced cognitive impairment will be valuable for early diagnosis, interventions, and prevention of further cognitive defects induced by hypertension.

The impact of dyslipidemia and hyperhomocysteinemia on the development of arterial hypertension

“…Endothelial dysfunction, as the initial event of atherosclerosis, is also the cause of arterial hypertension. With advancing age, compensatory mechanisms to maintain lower levels of homocysteine in the blood are insufficient, leading to elevated homocysteine in older individuals, further increasing cardiovascular risk 16 . Additionally, several pharmacologically active compounds increase homocysteine levels, such as antifolates, methotrexate, nitric oxide oxidizers, L-DOPA, hormone therapy, antiepileptics, and bile acid derivatives.…”

“…Endotelna disfunkcija kao početni događaj ateroskleroze istovremeno je uzrok i arterijske hipertenzije. Sa godinama života kompenzatorni mehanizmi za očuvanje niže vrednosti homocisteina u krvi su nedovoljni, pa starije osobe često imaju visok homocistein, što dodatno povećava kardiovaskularni rizik 16 . Takođe, nekoliko farmakološki aktivnih jedinjenja povećava nivo homocisteina, kao na primer antifolati, metotreksat, oksidi azota, L-DOPA, hormonska terapija, antiepileptici, derivati žučnih kiselina.…”

“…Hiperhomocisteinemija izaziva proizvodnju proinflamatornih citokina, odnosno interleukina-1β i interleukina-6, faktora nekroze tumora-α (Tumor Necrosis Factor, TNFα), monocitnog hemoatraktantnog proteina 1 (Monocyte Chemoattractant Protein-1, MCP-1) i intracelularnog adhezionog molekula-1 (Intercellular Adhesion Molecule-1, ICAM-1), što dovodi do povećanog oksidativnog oštećenja 16 . Postoje suprotstavljeni izveštaji o povezanosti između vrednosti homocisteina i učestalosti kardiovaskularnih bolesti.…”

Integrating transcriptomics and metabolomics to analyze the mechanism of hypertension-induced hippocampal injury

“…Homocysteine-mediated aberrant DNA methylation contributes to the development of hypertension. Homocysteine can also cause oxidative stress by decreasing endothelial NO concentrations ( Wan et al, 2022 ). In addition, homocysteine can increase vascular thickness and arterial blood pressure to influence hypertension ( Steed and Tyagi, 2011 ).…”

The study of relationships between clinical syndromes and gene polymorphisms of ACE and AT2R1 genes in patients with chronic vascular encephalopathy

“…Клінічний синдром Залежність клінічних синдромів від частоти алелів генів АСЕ та AT2R1 у пацієнтів з ХСЕ обґрунтована важливим значенням ренін-ангіотензин-альдостеронової системи (РААС) у центральній нервовій системі, оскільки її інгібування може зменшити швидкість зниження когнітивних функцій у пацієнтів з ХСЕ [16]. Ангіотензинперетворювальний фермент впливає на метаболізм ангіотензину в системі РААС, а інгібітори цього ферменту пригнічують активацію мікроглії та зберігають цілісність дендритів і когнітивну функцію [17].…”