HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 290/5/H1988    most recent 00344.2005v1 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 Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Robinson, W. P. Articles by Rich, P. B. Search for Related Content PubMed PubMed Citation Articles by Robinson, W. P., III Articles by Rich, P. B.

ATP stimulates MMP-2 release from human aortic smooth muscle cells via JNK signaling pathway

¹Department of Surgery, ²Department of Medicine, and ³Carolina Cardiovascular Biology Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina

Submitted 6 April 2005 ; accepted in final form 8 December 2005

Aortic smooth muscle cell release of matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) has been implicated in aortic aneurysm pathogenesis, but proximal modulation of release is poorly understood. Extracellular nucleotides regulate vascular smooth muscle cell metabolism in response to physiochemical stresses, but nucleotide modulation of MMP and/or TIMP release has not been reported. We hypothesized that nucleotides modulate MMP-2 and TIMP-2 release from human aortic smooth muscle cells (HASMCs) via distinct purinergic receptors and signaling pathways. We exposed HASMCs to exogenous ATP and other nucleotides with and without interleukin-1 (IL-1). HASMCs were pretreated in some experiments with apyrase, which degrades ATP, and inhibitors of ERK1/2, JNK, and p38 MAPK. MMP-2 and TIMP-2 released into supernatant were assessed using ELISA and Western blotting. ATP, adenosine, and UTP significantly stimulated MMP-2 release in the presence of IL-1 (300 nM ATP: 181 ± 22%, P = 0.003; 30 µm adenosine: 244 ± 150%, P = 0.001; and 200 µm UTP: 153 ± 40%, P = 0.015; vs. 100% constitutive). ATP also stimulated MMP-2 release in the absence of IL-1 (100 µm ATP: 148 ± 38% vs. 100% constitutive). Apyrase significantly reduced ATP-stimulated MMP-2 release (apyrase + 500 nM ATP: 59 ± 3% vs. 124 ± 7% with 500 nM ATP). Rank-order agonist potency for MMP-2 release was consistent with ATP activation of PAY and PAY receptors. ATP induced phosphorylation of intracellular JNK, and inhibition of the JNK pathway blocked ATP-stimulated MMP-2 release, indicating signaling via this pathway. Nucleotides are thus novel stimulants of MMP-2 release from HASMCs and may provide a mechanistic link between physiochemical stress in the aorta and aneurysms, especially in the context of inflammation.

abdominal aortic aneurysm; adenosine 5'-triphosphate; matrix metalloproteinase; extracellular nucleotides; mitogen-activated protein kinase; purines

This article has been cited by other articles:

				K. Enjyoji, K. Kotani, C. Thukral, B. Blumel, X. Sun, Y. Wu, M. Imai, D. Friedman, E. Csizmadia, W. Bleibel, et al. Deletion of Cd39/Entpd1 Results in Hepatic Insulin Resistance Diabetes, September 1, 2008; 57(9): 2311 - 2320. [Abstract] [Full Text] [PDF]

				I-C. Wang, Y.-J. Chen, D. E. Hughes, T. Ackerson, M. L. Major, V. V. Kalinichenko, R. H. Costa, P. Raychaudhuri, A. L. Tyner, and L. F. Lau FoxM1 Regulates Transcription of JNK1 to Promote the G1/S Transition and Tumor Cell Invasiveness J. Biol. Chem., July 25, 2008; 283(30): 20770 - 20778. [Abstract] [Full Text] [PDF]