title: Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness.
abstract: BACKGROUND
  Although an age-related decrease in NO bioavailability contributes to vascular stiffness, the underlying molecular mechanisms remain incompletely understood. We hypothesize that NO constrains the activity of the matrix crosslinking enzyme tissue transglutaminase (TG2) via S-nitrosylation in young vessels, a process that is reversed in aging.
  
  
  OBJECTIVE
  We sought to determine whether endothelium-dependent NO regulates TG2 activity by S-nitrosylation and whether this contributes to age-related vascular stiffness.
  
  
  RESULTS
  We first demonstrate that NO suppresses activity and increases S-nitrosylation of TG2 in cellular models. Next, we show that nitric oxide synthase (NOS) inhibition leads to increased surface and extracellular matrix-associated TG2. We then demonstrate that endothelium-derived bioactive NO primarily mediates its effects through TG2, using TG2(-/-) mice chronically treated with the NOS inhibitor l-N(G)-nitroarginine methyl ester (L-NAME). We confirm that TG2 activity is modulated by endothelium-derived bioactive NO in young rat aorta. In aging rat aorta, although TG2 expression remains unaltered, its activity increases and S-nitrosylation decreases. Furthermore, TG2 inhibition decreases vascular stiffness in aging rats. Finally, TG2 activity and matrix crosslinks are augmented with age in human aorta, whereas abundance remains unchanged.
  
  
  CONCLUSIONS
  Decreased S-nitrosylation of TG2 and increased TG activity lead to enhanced matrix crosslinking and contribute to vascular stiffening in aging. TG2 appears to be the member of the transglutaminase family primarily contributing to this phenotype. Inhibition of TG2 could thus represent a therapeutic target for age-associated vascular stiffness and isolated systolic hypertension.
authors.affiliation: Johns Hopkins University School of Medicine, 720 Rutland Ave, Traylor 621, Baltimore, MD 21205, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Santhanam
authors.forename: Eric C
authors.initials: EC
authors.lastname: Tuday
authors.forename: Alanah K
authors.initials: AK
authors.lastname: Webb
authors.forename: Phillip
authors.initials: P
authors.lastname: Dowzicky
authors.forename: Jae Hyung
authors.initials: JH
authors.lastname: Kim
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Oh
authors.forename: Gautam
authors.initials: G
authors.lastname: Sikka
authors.forename: Maggie
authors.initials: M
authors.lastname: Kuo
authors.forename: Marc K
authors.initials: MK
authors.lastname: Halushka
authors.forename: Anne M
authors.initials: AM
authors.lastname: Macgregor
authors.forename: Jessilyn
authors.initials: J
authors.lastname: Dunn
authors.forename: Sarah
authors.initials: S
authors.lastname: Gutbrod
authors.forename: David
authors.initials: D
authors.lastname: Yin
authors.forename: Artin
authors.initials: A
authors.lastname: Shoukas
authors.forename: Daniel
authors.initials: D
authors.lastname: Nyhan
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Flavahan
authors.forename: Alexey M
authors.initials: AM
authors.lastname: Belkin
authors.forename: Dan E
authors.initials: DE
authors.lastname: Berkowitz
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000473:pathology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D041681:NIH 3T3 Cells; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051381:Rats; D011916:Rats, Inbred F344; D011503:Transglutaminases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C000717609:Tgm2 protein, rat; D009569:Nitric Oxide; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins