Mitochondrial mechanism of oxidative stress and systemic hypertension in hyperhomocysteinemia.
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.
Tyagi
Neetu
N
Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. s0tyag01@louisville.edu
Moshal
Karni S
KS
Ovechkin
Alexander V
AV
Rodriguez
Walter
W
Steed
Mesia
M
Henderson
Brooke
B
Roberts
Andrew M
AM
Joshua
Irving G
IG
Tyagi
Suresh C
SC
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
D017382:Reactive Oxygen Species; D006710:Homocysteine