Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness

Lakshmi Santhanam, Eric C. Tuday, Alanah K. Webb, Phillip Dowzicky, Jae Hyung Kim, Young Jun Oh, Gautam Sikka, Maggie Kuo, Marc K Halushka, Anne M. MacGregor, Jessilyn Dunn, Sarah Gutbrod, David Yin, Artin A Shoukas, Daniel Nyhan, Nicholas Flavahan, Alexey M. Belkin, Dan E Berkowitz

Research output: Contribution to journalArticle

Abstract

Rationale: 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. Methods and 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-NG-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.

Original languageEnglish (US)
Pages (from-to)117-125
Number of pages9
JournalCirculation Research
Volume107
Issue number1
DOIs
StatePublished - Jul 9 2010

Fingerprint

Vascular Stiffness
Endothelium
Aorta
Nitric Oxide Synthase
Transglutaminases
NG-Nitroarginine Methyl Ester
Biological Availability
Extracellular Matrix
Blood Vessels
Hypertension
Phenotype
transglutaminase 2
Enzymes
Inhibition (Psychology)
Therapeutics

Keywords

  • Aging
  • S-nitrosation
  • S-nitrosylation
  • Tissue transglutaminase
  • Vascular stiffness

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness. / Santhanam, Lakshmi; Tuday, Eric C.; Webb, Alanah K.; Dowzicky, Phillip; Kim, Jae Hyung; Oh, Young Jun; Sikka, Gautam; Kuo, Maggie; Halushka, Marc K; MacGregor, Anne M.; Dunn, Jessilyn; Gutbrod, Sarah; Yin, David; Shoukas, Artin A; Nyhan, Daniel; Flavahan, Nicholas; Belkin, Alexey M.; Berkowitz, Dan E.

In: Circulation Research, Vol. 107, No. 1, 09.07.2010, p. 117-125.

Research output: Contribution to journalArticle

Santhanam, L, Tuday, EC, Webb, AK, Dowzicky, P, Kim, JH, Oh, YJ, Sikka, G, Kuo, M, Halushka, MK, MacGregor, AM, Dunn, J, Gutbrod, S, Yin, D, Shoukas, AA, Nyhan, D, Flavahan, N, Belkin, AM & Berkowitz, DE 2010, 'Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness', Circulation Research, vol. 107, no. 1, pp. 117-125. https://doi.org/10.1161/CIRCRESAHA.109.215228
Santhanam, Lakshmi ; Tuday, Eric C. ; Webb, Alanah K. ; Dowzicky, Phillip ; Kim, Jae Hyung ; Oh, Young Jun ; Sikka, Gautam ; Kuo, Maggie ; Halushka, Marc K ; MacGregor, Anne M. ; Dunn, Jessilyn ; Gutbrod, Sarah ; Yin, David ; Shoukas, Artin A ; Nyhan, Daniel ; Flavahan, Nicholas ; Belkin, Alexey M. ; Berkowitz, Dan E. / Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness. In: Circulation Research. 2010 ; Vol. 107, No. 1. pp. 117-125.
@article{cdbc51014d9c468b9f214cb525b96b4d,
title = "Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness",
abstract = "Rationale: 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. Methods and 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-NG-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.",
keywords = "Aging, S-nitrosation, S-nitrosylation, Tissue transglutaminase, Vascular stiffness",
author = "Lakshmi Santhanam and Tuday, {Eric C.} and Webb, {Alanah K.} and Phillip Dowzicky and Kim, {Jae Hyung} and Oh, {Young Jun} and Gautam Sikka and Maggie Kuo and Halushka, {Marc K} and MacGregor, {Anne M.} and Jessilyn Dunn and Sarah Gutbrod and David Yin and Shoukas, {Artin A} and Daniel Nyhan and Nicholas Flavahan and Belkin, {Alexey M.} and Berkowitz, {Dan E}",
year = "2010",
month = "7",
day = "9",
doi = "10.1161/CIRCRESAHA.109.215228",
language = "English (US)",
volume = "107",
pages = "117--125",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - Decreased S-nitrosylation of tissue transglutaminase contributes to age-related increases in vascular stiffness

AU - Santhanam, Lakshmi

AU - Tuday, Eric C.

AU - Webb, Alanah K.

AU - Dowzicky, Phillip

AU - Kim, Jae Hyung

AU - Oh, Young Jun

AU - Sikka, Gautam

AU - Kuo, Maggie

AU - Halushka, Marc K

AU - MacGregor, Anne M.

AU - Dunn, Jessilyn

AU - Gutbrod, Sarah

AU - Yin, David

AU - Shoukas, Artin A

AU - Nyhan, Daniel

AU - Flavahan, Nicholas

AU - Belkin, Alexey M.

AU - Berkowitz, Dan E

PY - 2010/7/9

Y1 - 2010/7/9

N2 - Rationale: 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. Methods and 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-NG-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.

AB - Rationale: 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. Methods and 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-NG-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.

KW - Aging

KW - S-nitrosation

KW - S-nitrosylation

KW - Tissue transglutaminase

KW - Vascular stiffness

UR - http://www.scopus.com/inward/record.url?scp=77954761224&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954761224&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.109.215228

DO - 10.1161/CIRCRESAHA.109.215228

M3 - Article

C2 - 20489165

AN - SCOPUS:77954761224

VL - 107

SP - 117

EP - 125

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 1

ER -