Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness.
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.
Santhanam
Lakshmi
L
Johns Hopkins University School of Medicine, 720 Rutland Ave, Traylor 621, Baltimore, MD 21205, USA.
Tuday
Eric C
EC
Webb
Alanah K
AK
Dowzicky
Phillip
P
Kim
Jae Hyung
JH
Oh
Young Jun
YJ
Sikka
Gautam
G
Kuo
Maggie
M
Halushka
Marc K
MK
Macgregor
Anne M
AM
Dunn
Jessilyn
J
Gutbrod
Sarah
S
Yin
David
D
Shoukas
Artin
A
Nyhan
Daniel
D
Flavahan
Nicholas A
NA
Belkin
Alexey M
AM
Berkowitz
Dan E
DE
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*
C000717609:Tgm2 protein, rat; D009569:Nitric Oxide; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins