title: Mitochondrial mechanism of oxidative stress and systemic hypertension in hyperhomocysteinemia.
abstract: Formation of homocysteine (Hcy) is the constitutive process of gene methylation. Hcy is primarily synthesized by de-methylation of methionine, in which s-adenosyl-methionine (SAM) is converted to s-adenosyl-homocysteine (SAH) by methyltransferase (MT). SAH is then hydrolyzed to Hcy and adenosine by SAH-hydrolase (SAHH). The accumulation of Hcy leads to increased cellular oxidative stress in which mitochondrial thioredoxin, and peroxiredoxin are decreased and NADH oxidase activity is increased. In this process, Ca2+-dependent mitochondrial nitric oxide synthase (mtNOS) and calpain are induced which lead to cytoskeletal de-arrangement and cellular remodeling. This process generates peroxinitrite and nitrotyrosine in contractile proteins which causes vascular dysfunction. Chronic exposure to Hcy instigates endothelial and vascular dysfunction and increases vascular resistance causing systemic hypertension. To compensate, the heart increases its load which creates adverse cardiac remodeling in which the elastin/collagen ratio is reduced, causing cardiac stiffness and diastolic heart failure in hyperhomocysteinemia.
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. s0tyag01@louisville.edu
authors.forename: Neetu
authors.initials: N
authors.lastname: Tyagi
authors.forename: Karni S
authors.initials: KS
authors.lastname: Moshal
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Ovechkin
authors.forename: Walter
authors.initials: W
authors.lastname: Rodriguez
authors.forename: Mesia
authors.initials: M
authors.lastname: Steed
authors.forename: Brooke
authors.initials: B
authors.lastname: Henderson
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Roberts
authors.forename: Irving G
authors.initials: IG
authors.lastname: Joshua
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
mesh_terms: D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications* / Q000378:metabolism*; D006973:Hypertension / Q000150:complications* / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D006710:Homocysteine