title: Nitric oxide regulates tissue transglutaminase localization and function in the vasculature.
abstract: The multifunctional enzyme tissue transglutaminase (TG2) contributes to the development and progression of several cardiovascular diseases. Extracellular rather than intracellular TG2 is enzymatically active, however, the mechanism by which it is exported out of the cell remains unknown. Nitric oxide (NO) is shown to constrain TG2 externalization in endothelial and fibroblast cells. Here, we examined the role of both exogenous and endogenous (endothelial cell-derived) NO in regulating TG2 localization in vascular cells and tissue. NO synthase inhibition in endothelial cells (ECs) using N-nitro L-arginine methyl ester (L-NAME) led to a time-dependent decrease in S-nitrosation and increase in externalization of TG2. Laminar shear stress led to decreased extracellular TG2 in ECs. S-nitrosoglutathione treatment led to decreased activity and externalization of TG2 in human aortic smooth muscle and fibroblast (IMR90) cells. Co-culture of these cells with ECs resulted in increased S-nitrosation and decreased externalization and activity of TG2, which was reversed by L-NAME. Aged Fischer 344 rats had higher tissue scaffold-associated TG2 compared to young. NO regulates intracellular versus extracellular TG2 localization in vascular cells and tissue, likely via S-nitrosation. This in part, explains increased TG2 externalization and activity in aging aorta.
authors: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 720 Rutland Ave, Ross 1150, Baltimore, MD 21205, USA.
authors: Simran K
authors: SK
authors: Jandu
authors: Alanah K
authors: AK
authors: Webb
authors: Alina
authors: A
authors: Pak
authors: Baris
authors: B
authors: Sevinc
authors: Daniel
authors: D
authors: Nyhan
authors: Alexey M
authors: AM
authors: Belkin
authors: Nicholas A
authors: NA
authors: Flavahan
authors: Dan E
authors: DE
authors: Berkowitz
authors: Lakshmi
authors: L
authors: Santhanam
mesh_terms: D000367:Age Factors; D000818:Animals; D001011:Aorta / Q000166:cytology; D002460:Cell Line; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000166:cytology; D005109:Extracellular Matrix / Q000201:enzymology; D005347:Fibroblasts / Q000201:enzymology; D019204:GTP-Binding Proteins; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000502:physiology; D015538:Nitrosation; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D021381:Protein Transport; D051381:Rats; D011916:Rats, Inbred F344; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: C000717609:Tgm2 protein, rat; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D019331:NG-Nitroarginine Methyl Ester