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Published on: June 3, 2014
Epigenetic regulation of aortic remodeling in hyperhomocysteinemia
Nithya Narayanan1, Sathnur Basappa Pushpakumar1, Srikanth Givvimani1
1Department of Physiology and Biophysics, University of Louisville School of Medicine, and.
Insights
DNA methylation inhibition with 5-aza-2'-deoxycytidine (Aza) normalized blood pressure in hyperhomocysteinemia (HHcy) mice. Aza treatment reduced aortic collagen deposition and improved vascular function, mitigating hypertension associated with HHcy.
Area of Science:
- Cardiovascular Research
- Epigenetics
- Hypertension Pathophysiology
Background:
- Hyperhomocysteinemia (HHcy) is linked to hypertension and aortic disease.
- HHcy disrupts matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) balance, causing aortic collagen accumulation and stiffness.
- Epigenetic regulation via DNA methylation is implicated in extracellular matrix (ECM) remodeling in HHcy.
Purpose of the Study:
- To investigate if 5-aza-2 -deoxycytidine (Aza), a DNA methyltransferase (DNMT1) inhibitor, can reduce hypertension by regulating aortic ECM remodeling in HHcy.
- To assess the effects of Aza on blood pressure, aortic structure, vascular function, and ECM remodeling markers in HHcy mice.
Main Methods:
- Wild-type and cystathionine β-synthase (CBS)(+/-) HHcy mice were treated with Aza (0.5 mg/kg).
- Evaluated plasma homocysteine (Hcy) levels, blood pressure (BP), aortic ultrasound parameters (resistive index, wall-to-lumen ratio), and vascular reactivity.
- Analyzed aortic collagen deposition via histology and quantified expression of DNMT1, MMP9, TIMP1, SAHH, and MTHFR.
Main Results:
- Aza treatment normalized plasma Hcy levels and BP in HHcy mice.
- Aortic ultrasound revealed reduced resistive index and wall-to-lumen ratio post-Aza treatment.
- Histology showed decreased collagen deposition, improved vascular responses, and altered expression of key epigenetic and remodeling enzymes (DNMT1, MMP9, TIMP1, SAHH, MTHFR).
Conclusions:
- Reduction of DNA methylation by Aza mitigates hypertension in HHcy.
- Aza treatment ameliorates adverse aortic remodeling by modulating ECM components and epigenetic factors.
- Targeting DNA methylation presents a potential therapeutic strategy for hypertension associated with HHcy.
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.
