This Article Full Text Full Text (PDF) 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 Durante, W. Articles by Schafer, A. I. Search for Related Content PubMed PubMed Citation Articles by Durante, W. Articles by Schafer, A. I. Related Collections Smooth muscle proliferation and differentiation Chronic ischemic heart disease

(Circulation. 2001;103:1121.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Transforming Growth Factor-ß₁ Stimulates L-Arginine Transport and Metabolism in Vascular Smooth Muscle Cells

Role in Polyamine and Collagen Synthesis

William Durante, PhD; Lan Liao, MS; Sylvia V. Reyna, BS; Kelly J. Peyton, MA; Andrew I. Schafer, MD

From Houston VA Medical Center and the Departments of Medicine (W.D., L.L., S.V.R., K.J.P., A.I.S.) and Pharmacology (W.D.), Baylor College of Medicine, Houston, Tex.

Correspondence to William Durante, PhD, Houston VA Medical Center, Building 109, Room 130, 2002 Holcombe Blvd, Houston, TX 77030. E-mail wdurante{at}bcm.tmc.edu

Background—Transforming growth factor-ß₁ (TGF-ß₁) contributes to arterial remodeling by stimulating vascular smooth muscle cell (VSMC) growth and collagen synthesis at sites of vascular injury. Because L-arginine is metabolized to growth-stimulatory polyamines and to the essential collagen precursor L-proline, we examined whether TGF-ß₁ regulates the transcellular transport and metabolism of L-arginine by VSMCs.

Methods and Results—TGF-ß₁ increased L-arginine uptake, and this was associated with a selective increase in cationic amino acid transporter-1 (CAT-1) mRNA. In addition, TGF-ß₁ stimulated L-arginine metabolism by inducing arginase I mRNA and arginase activity. TGF-ß₁ also stimulated L-ornithine catabolism by elevating ornithine decarboxylase (ODC) and ornithine aminotransferase (OAT) activity. TGF-ß₁ markedly increased the capacity of VSMCs to generate the polyamine putrescine and L-proline from extracellular L-arginine. The TGF-ß₁–mediated increase in putrescine and L-proline production was reversed by methyl-L-arginine, a competitive inhibitor of cationic amino acid transport, or by hydroxy-L-arginine, an arginase inhibitor. Furthermore, the formation of putrescine was inhibited by the ODC inhibitor -difluoromethylornithine, and L-proline generation was blocked by the OAT inhibitor L-canaline. L-Canaline also inhibited TGF-ß₁–stimulated type I collagen synthesis.

Conclusions—These results demonstrate that TGF-ß₁ stimulates polyamine and L-proline synthesis by inducing the genes that regulate the transport and metabolism of L-arginine. In addition, they show that TGF-ß₁–stimulated collagen production is dependent on L-proline formation. The ability of TGF-ß₁ to upregulate L-arginine transport and direct its metabolism to polyamines and L-proline may contribute to arterial remodeling at sites of vascular damage.

Key Words: muscle, smooth • amino acids • collagen

This article has been cited by other articles:

				B. Chen, A. E. Calvert, H. Cui, and L. D. Nelin Hypoxia promotes human pulmonary artery smooth muscle cell proliferation through induction of arginase Am J Physiol Lung Cell Mol Physiol, December 1, 2009; 297(6): L1151 - L1159. [Abstract] [Full Text] [PDF]

				J. Belik, D. Stevens, J. Pan, D. Shehnaz, C. Ibrahim, C. Kantores, J. Ivanovska, H. Grasemann, and R. P. Jankov Chronic hypercapnia downregulates arginase expression and activity and increases pulmonary arterial smooth muscle relaxation in the newborn rat Am J Physiol Lung Cell Mol Physiol, October 1, 2009; 297(4): L777 - L784. [Abstract] [Full Text] [PDF]

				U. Mabalirajan, J. Aich, A. Agrawal, and B. Ghosh Mepacrine inhibits subepithelial fibrosis by reducing the expression of arginase and TGF-{beta}1 in an extended subacute mouse model of allergic asthma Am J Physiol Lung Cell Mol Physiol, September 1, 2009; 297(3): L411 - L419. [Abstract] [Full Text] [PDF]

				K. J. Peyton, D. Ensenat, M. A. Azam, A. N. Keswani, S. Kannan, X.-m. Liu, H. Wang, D. A. Tulis, and W. Durante Arginase Promotes Neointima Formation in Rat Injured Carotid Arteries Arterioscler Thromb Vasc Biol, April 1, 2009; 29(4): 488 - 494. [Abstract] [Full Text] [PDF]

				L. Santhanam, D. W. Christianson, D. Nyhan, and D. E. Berkowitz Arginase and vascular aging J Appl Physiol, November 1, 2008; 105(5): 1632 - 1642. [Abstract] [Full Text] [PDF]

				S. Belmadani, M. Zerfaoui, H. A. Boulares, D. I. Palen, and K. Matrougui Microvessel vascular smooth muscle cells contribute to collagen type I deposition through ERK1/2 MAP kinase, {alpha}v{beta}3-integrin, and TGF-{beta}1 in response to ANG II and high glucose Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H69 - H76. [Abstract] [Full Text] [PDF]

				J. Belik, D. Shehnaz, J. Pan, and H. Grasemann Developmental changes in arginase expression and activity in the lung Am J Physiol Lung Cell Mol Physiol, March 1, 2008; 294(3): L498 - L504. [Abstract] [Full Text] [PDF]

				J. Dumont, M. Zureik, D. Cottel, M. Montaye, P. Ducimetiere, P. Amouyel, and T. Brousseau Association of arginase 1 gene polymorphisms with the risk of myocardial infarction and common carotid intima media thickness J. Med. Genet., August 1, 2007; 44(8): 526 - 531. [Abstract] [Full Text] [PDF]

				S. M. Morris Jr. Arginine Metabolism: Boundaries of Our Knowledge J. Nutr., June 1, 2007; 137(6): 1602S - 1609S. [Abstract] [Full Text] [PDF]

				L. A. Holowatz and W. L. Kenney Up-regulation of arginase activity contributes to attenuated reflex cutaneous vasodilatation in hypertensive humans J. Physiol., June 1, 2007; 581(2): 863 - 872. [Abstract] [Full Text] [PDF]

				S. Sakao, L. Taraseviciene-Stewart, K. Wood, C. D. Cool, and N. F. Voelkel Apoptosis of pulmonary microvascular endothelial cells stimulates vascular smooth muscle cell growth Am J Physiol Lung Cell Mol Physiol, September 1, 2006; 291(3): L362 - L368. [Abstract] [Full Text] [PDF]

				G. S. Getz and C. A. Reardon Arginine/Arginase NO NO NO Arterioscler Thromb Vasc Biol, February 1, 2006; 26(2): 237 - 239. [Full Text] [PDF]

				D. Teupser, R. Burkhardt, W. Wilfert, I. Haffner, K. Nebendahl, and J. Thiery Identification of Macrophage Arginase I as a New Candidate Gene of Atherosclerosis Resistance Arterioscler Thromb Vasc Biol, February 1, 2006; 26(2): 365 - 371. [Abstract] [Full Text] [PDF]

				S. M Morris JR Arginine metabolism in vascular biology and disease Vascular Medicine, July 1, 2005; 10(1_suppl): S83 - S87. [Abstract] [PDF]

				S. M Morris Jr Arginine metabolism in vascular biology and disease Vascular Medicine, May 1, 2005; 10(2_suppl): S83 - S87. [Abstract] [PDF]

				A. Rotmann, D. Strand, U. Martine, and E. I. Closs Protein Kinase C Activation Promotes the Internalization of the Human Cationic Amino Acid Transporter hCAT-1: A NEW REGULATORY MECHANISM FOR hCAT-1 ACTIVITY J. Biol. Chem., December 24, 2004; 279(52): 54185 - 54192. [Abstract] [Full Text] [PDF]

				E. I. Closs, A. Simon, N. Vekony, and A. Rotmann Plasma Membrane Transporters for Arginine J. Nutr., October 1, 2004; 134(10): 2752S - 2759S. [Abstract] [Full Text] [PDF]

				K. C. Fertuck, J. E. Eckel, C. Gennings, and T. R. Zacharewski Identification of temporal patterns of gene expression in the uteri of immature, ovariectomized mice following exposure to ethynylestradiol Physiol Genomics, October 17, 2003; 15(2): 127 - 141. [Abstract] [Full Text] [PDF]

				P. M. Martin, A. E. Sutherland, and L. J. Van Winkle Amino Acid Transport Regulates Blastocyst Implantation Biol Reprod, October 1, 2003; 69(4): 1101 - 1108. [Abstract] [Full Text] [PDF]

				J.-M. Li, L. M. Fan, A. Shah, and G. Brooks Targeting {alpha}v{beta}3 and {alpha}5{beta}1 for gene delivery to proliferating VSMCs: synergistic effect of TGF-{beta}1 Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H1123 - H1131. [Abstract] [Full Text] [PDF]

				M. Endo, S. Oyadomari, Y. Terasaki, M. Takeya, M. Suga, M. Mori, and T. Gotoh Induction of arginase I and II in bleomycin-induced fibrosis of mouse lung Am J Physiol Lung Cell Mol Physiol, August 1, 2003; 285(2): L313 - L321. [Abstract] [Full Text] [PDF]

				M. E. Ramos-Nino, L. Scapoli, M. Martinelli, S. Land, and B. T. Mossman Microarray Analysis and RNA Silencing Link fra-1 to cd44 and c-met Expression in Mesothelioma Cancer Res., July 1, 2003; 63(13): 3539 - 3545. [Abstract] [Full Text] [PDF]

				G. E. Mann, D. L. Yudilevich, and L. Sobrevia Regulation of Amino Acid and Glucose Transporters in Endothelial and Smooth Muscle Cells Physiol Rev, January 1, 2003; 83(1): 183 - 252. [Abstract] [Full Text] [PDF]

				D. Teixeira, M. L. Santaolaria, V. Meneu, and E. Alonso Dietary Arginine Slightly and Variably Affects Tissue Polyamine Levels in Male Swiss Albino Mice J. Nutr., December 1, 2002; 132(12): 3715 - 3720. [Abstract] [Full Text] [PDF]