This Article Full Text Full Text (PDF) Data Supplement Correction (v102,pe106) All Versions of this Article: 102/5/529    most recent CIRCRESAHA.107.154260v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Johnson, K. A. Articles by Terkeltaub, R. A. Search for Related Content PubMed PubMed Citation Articles by Johnson, K. A. Articles by Terkeltaub, R. A. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Related Collections Cell biology/structural biology Gene regulation Smooth muscle proliferation and differentiation Related Article

(Circulation Research. 2008;102:529.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Transglutaminase 2 Is Central to Induction of the Arterial Calcification Program by Smooth Muscle Cells

Kristen A. Johnson, Monika Polewski, Robert A. Terkeltaub

From the Veterans Affairs Medical Center, University of California at San Diego, La Jolla.

Correspondence to R. Terkeltaub, MD, VA Medical Center, 3350 La Jolla Village Dr, San Diego, CA 92161. E-mail rterkeltaub{at}ucsd.edu

Arterial calcification is a phenotype of vascular repair in atherosclerosis, diabetes, hyperphosphatemic renal failure, and aging. Arterial calcification is modulated by transition of arterial smooth muscle cells (SMCs) from contractile to chondro–osseous differentiation programmed in response to increases in P_i, bone morphogenetic protein-2, and certain other stimuli. Transglutaminase (TG)2 release modulates tissue repair, partly by transamidation-catalyzed covalent crosslinking of extracellular matrix substrates. TG2 regulates cultured SMC differentiation, resistance artery remodeling to vasoconstriction, and atherosclerotic lesion size. Here, TG2 expression was required for the majority of TG activity in mouse and human aortic SMCs. TG2^–/– SMCs lost the capacity for P_i donor–induced formation of multicellular bone-like nodules and for increased expression of the type III sodium–dependent P_i cotransporter Pit-1 and certain osteoblast and chondrocyte genes (tissue-nonspecific alkaline phosphatase, the osteoblast master transcription factor runx2, and chondrocyte-restricted aggrecan), and for P_i donor– and bone morphogenetic protein-2–induced calcification. Uniquely in TG2^–/– SMCs, P_i donor treatment increased expression of the physiological SMC chondro–osseous differentiation and calcification inhibitors osteoprotegerin, matrix Gla protein, and osteopontin. Conversely, TG2^–/– SMCs, unlike wild-type SMCs, failed to maintain contractile differentiation on laminin. Exogenous catalytically active TG2 augmented calcification by TG2^–/– SMC in response to P_i donor treatment. TG2 expression also drove P_i-stimulated calcification of mouse aortic ring organ cultures, which was suppressed by the TG2 catalytic site-specific inhibitor Boc-DON-Gln-Ile-Val-OMe (10 µmol/L). Our results suggest that TG2 release in injured arteries is critical for programming chondro–osseous SMC differentiation and calcification in response to increased P_i and bone morphogenetic protein-2.

Key Words: smooth muscle cells • atherosclerosis • osteopontin • matrix Gla protein • osteoprotegerin • laminin

Related Article:

A Vascular Bone Collector: Arterial Calcification Requires Tissue-Type Transglutaminase

Ed VanBavel and Erik N.T.P. Bakker
Circ. Res. 2008 102: 507-509. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				J. D. Miller, R. M. Weiss, K. M. Serrano, R. M. Brooks II, C. J. Berry, K. Zimmerman, S. G. Young, and D. D. Heistad Lowering Plasma Cholesterol Levels Halts Progression of Aortic Valve Disease in Mice Circulation, May 26, 2009; 119(20): 2693 - 2701. [Abstract] [Full Text] [PDF]

				R. Terkeltaub Macrophage Glucocorticoid Receptors Join the Intercellular Dialogue in Atherosclerotic Lesion Calcification Arterioscler. Thromb. Vasc. Biol., December 1, 2008; 28(12): 2096 - 2098. [Full Text] [PDF]

				E. VanBavel and E. N.T.P. Bakker A Vascular Bone Collector: Arterial Calcification Requires Tissue-Type Transglutaminase Circ. Res., March 14, 2008; 102(5): 507 - 509. [Full Text] [PDF]