Epigenetic regulation of aortic remodeling in hyperhomocysteinemia

Abstract

Hyperhomocysteinemia (HHcy) is prevalent in patients with hypertension and is an independent risk factor for aortic pathologies. HHcy is known to cause an imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), leading to the accumulation of collagen in the aorta and resulting in stiffness and development of hypertension. Although the exact mechanism of extracellular matrix (ECM) remodeling is unclear, emerging evidence implicates epigenetic regulation involving DNA methylation. Our purpose was to investigate whether 5-aza-2'-deoxycytidine (Aza), a DNA methyltransferase (DNMT1) inhibitor, reduces high blood pressure (BP) by regulating aortic ECM remodeling in HHcy. Wild-type and cystathionine β-synthase (CBS)(+/-) HHcy mice were treated with Aza (0.5 mg/kg body weight). In HHcy mice, Aza treatment normalized the plasma homocysteine (Hcy) level and BP. Thoracic and abdominal aorta ultrasound revealed a reduction in the resistive index and wall-to-lumen ratio. Vascular response to phenylephrine, acetylcholine, and sodium nitroprusside improved after Aza in HHcy mice. Histology showed a marked reduction in collagen deposition in the aorta. Aza treatment decreased the expression of DNMT1, MMP9, TIMP1, and S-adenosyl homocysteine hydrolase (SAHH) and upregulated methylene tetrahydrofolate reductase (MTHFR). We conclude that reduction of DNA methylation by Aza in HHcy reduces adverse aortic remodeling to mitigate hypertension.

Hyperhomocysteinemia inhibits satellite cell regenerative capacity through p38 alpha/beta MAPK signaling

“…1) Association between HHcy and muscle weakness was reported both in the humans and in mouse models (24,26). 2) HHcy was associated with progressive decline in body weights both in humans and in mouse models (12,14,29). Notably, the CBSϪ/ϩ mice do not exhibit significant reduction in the body weights within 14 days of postpartum, but do exhibit significant reduction at around 3 mo of age.…”

“…However, the pups with heterozygous deletion for Cbs gene (CBSϪ/ϩ pups), which exhibit mild to moderate HHcy, did not show considerable reduction in overall body weights, suggesting the chronic nature of moderate HHcy effects on muscle mass (29). In adult mouse models of HHcy, the CBSϪ/ϩ mouse and CSE-deficient mouse, there was reduction in overall body weight (10,14,29). Several parallels suggested HHcy mediated inhibition of satellite cell proliferation: 1) HHcy was shown to enhance p38 MAPK signaling in different tissue types (19,28); 2) HHcy was demonstrated to enhance oxidative stress in skeletal muscles (10,25); and 3) HHcy was shown to induce myostatin, an inhibitor of myogenesis, in skeletal muscles (7).…”

Epigenetics of Arterial Hypertension

“…Ос-танній є інгібітором процесу метилювання. Гіпергомоцистеїнемія викликає дисбаланс між матриксними металопротеїназами і тканинними їх інгібіторами, що призводить до накопичення колагену в аорті і, в резуль-таті, -до її жорсткості та розвитку АГ [24]. Відомо про роль метаболічного синдрому та цукрового діабету у розвитку АГ.…”

Hyperhomocysteinemia: a missing link to dysfunctional HDL via paraoxanase-1

“…HHcy decreases eNOSdependent NO production and causes endothelial damage and dysfunction (Steed et al 2010). HHcy induces ECM remodeling, especially through matrix metalloproteinase-9 (MMP-9) and also decreases vascular gap junction proteins such as connexin-37 and -40 (Givvimani et al 2013;Narayanan et al 2014). HHcy has also been shown to stimulate asymmetric dimethylarginine (ADMA) and to downregulate Akt, eNOS, and dimethyl arginine dimethyl amino hydrolase 2 (DDAH2) (Yan et al 2010;Liu et al 2012).…”