PMID- 24739303 OWN - NLM STAT- MEDLINE DCOM- 20141006 LR - 20211021 IS - 1530-6860 (Electronic) IS - 0892-6638 (Print) IS - 0892-6638 (Linking) VI - 28 IP - 8 DP - 2014 Aug TI - Epigenetic regulation of aortic remodeling in hyperhomocysteinemia. PG - 3411-22 LID - 10.1096/fj.14-250183 [doi] AB - 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 beta-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. CI - (c) FASEB. FAU - Narayanan, Nithya AU - Narayanan N AD - Department of Physiology and Biophysics, University of Louisville School of Medicine, and. FAU - Pushpakumar, Sathnur Basappa AU - Pushpakumar SB AD - Department of Physiology and Biophysics, University of Louisville School of Medicine, and. FAU - Givvimani, Srikanth AU - Givvimani S AD - Department of Physiology and Biophysics, University of Louisville School of Medicine, and. FAU - Kundu, Sourav AU - Kundu S AD - Department of Physiology and Biophysics, University of Louisville School of Medicine, and. FAU - Metreveli, Naira AU - Metreveli N AD - Department of Physiology and Biophysics, University of Louisville School of Medicine, and. FAU - James, Dexter AU - James D AD - Department of Exercise Physiology, University of Louisville, Louisville, Kentucky, USA. FAU - Bratcher, Adrienne P AU - Bratcher AP AD - Department of Exercise Physiology, University of Louisville, Louisville, Kentucky, USA. FAU - Tyagi, Suresh C AU - Tyagi SC AD - Department of Physiology and Biophysics, University of Louisville School of Medicine, and s0tyag01@louisville.edu. LA - eng GR - R01 HL074185/HL/NHLBI NIH HHS/United States GR - R01 NS084823/NS/NINDS NIH HHS/United States GR - NS-084823/NS/NINDS NIH HHS/United States GR - R01HL074185-10/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20140416 PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (Extracellular Matrix Proteins) RN - 0 (Timp1 protein, mouse) RN - 0 (Tissue Inhibitor of Metalloproteinase-1) RN - 169D1260KM (Nitroprusside) RN - 1WS297W6MV (Phenylephrine) RN - 776B62CQ27 (Decitabine) RN - 9007-34-5 (Collagen) RN - EC 1.5.1.20 (Methylenetetrahydrofolate Reductase (NADPH2)) RN - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferase 1) RN - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases) RN - EC 2.1.1.37 (Dnmt1 protein, mouse) RN - EC 3.3.1.1 (Adenosylhomocysteinase) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - EC 3.4.24.35 (Mmp9 protein, mouse) RN - M801H13NRU (Azacitidine) RN - N9YNS0M02X (Acetylcholine) SB - IM MH - Acetylcholine/pharmacology MH - Adenosylhomocysteinase/biosynthesis/genetics MH - Animals MH - Aorta/chemistry/diagnostic imaging/drug effects/*physiopathology MH - Azacitidine/*analogs & derivatives/pharmacology MH - Collagen/metabolism MH - DNA (Cytosine-5-)-Methyltransferase 1 MH - DNA (Cytosine-5-)-Methyltransferases/antagonists & inhibitors/biosynthesis/genetics MH - *DNA Methylation/drug effects MH - Decitabine MH - Endothelium, Vascular/physiopathology MH - Epigenesis, Genetic/genetics/*physiology MH - Extracellular Matrix Proteins/metabolism MH - Gene Expression Regulation, Enzymologic/drug effects MH - Homocystinuria/complications/drug therapy/genetics MH - Hyperhomocysteinemia/complications/*genetics/physiopathology MH - Hypertension/etiology/genetics/*prevention & control MH - Male MH - Matrix Metalloproteinase 9/biosynthesis/genetics MH - Methylenetetrahydrofolate Reductase (NADPH2)/biosynthesis/genetics MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Nitroprusside/pharmacology MH - Phenylephrine/pharmacology MH - Tissue Inhibitor of Metalloproteinase-1/biosynthesis/genetics MH - Ultrasonography MH - Vascular Resistance/*drug effects/genetics PMC - PMC4101656 OTO - NOTNLM OT - 5-aza-2'-deoxycytidine OT - DNA methylation OT - extracellular matrix EDAT- 2014/04/18 06:00 MHDA- 2014/10/07 06:00 PMCR- 2015/08/01 CRDT- 2014/04/18 06:00 PHST- 2014/04/18 06:00 [entrez] PHST- 2014/04/18 06:00 [pubmed] PHST- 2014/10/07 06:00 [medline] PHST- 2015/08/01 00:00 [pmc-release] AID - fj.14-250183 [pii] AID - 14-250183 [pii] AID - 10.1096/fj.14-250183 [doi] PST - ppublish SO - FASEB J. 2014 Aug;28(8):3411-22. doi: 10.1096/fj.14-250183. Epub 2014 Apr 16.