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: 290/3/C883    most recent 00359.2005v1 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 Web of Science 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 Web of Science (24) Citing Articles via Google Scholar Google Scholar Articles by Moshal, K. S. Articles by Tyagi, S. C. Search for Related Content PubMed PubMed Citation Articles by Moshal, K. S. Articles by Tyagi, S. C.

RECEPTORS AND SIGNAL TRANSDUCTION

Regulation of homocysteine-induced MMP-9 by ERK1/2 pathway

Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky

Submitted 18 July 2005 ; accepted in final form 20 October 2005

Homocysteine (Hcy) induces matrix metalloproteinase (MMP)-9 in microvascular endothelial cells (MVECs). We hypothesized that the ERK1/2 signaling pathway is involved in Hcy-mediated MMP-9 expression. In cultured MVECs, Hcy induced activation of ERK, which was blocked by PD-98059 and U0126 (MEK inhibitors). Pretreatment with BAPTA-AM, staurosporine (PKC inhibitor), or Gö6976 (specific inhibitor for Ca²⁺-dependent PKC) abrogated ERK phosphorylation, suggesting the role of Ca²⁺ and Ca²⁺-dependent PKC in Hcy-induced ERK activation. ERK phosphorylation was suppressed by pertussis toxin (PTX), suggesting the involvement of G protein-coupled receptors (GPCRs) in initiating signal transduction by Hcy and leading to ERK activation. Pretreatment of MVECs with genistein, BAPTA-AM, or thapsigargin abrogated Hcy-induced ERK activation, suggesting the involvement of the PTK pathway in Hcy-induced ERK activation, which was mediated by intracellular Ca²⁺ pool depletion. ERK activation was attenuated by preincubation with N-acetylcysteine (NAC) and SOD, suggesting the role of oxidation in Hcy-induced ERK activation. Pretreatment with an ERK1/2 blocker (PD-98059), staurosporine, folate, or NAC modulated Hcy-induced MMP-9 activation as measured using zymography. Our results provide evidence that Hcy triggers the PTX-sensitive ERK1/2 signaling pathway, which is involved in the regulation of MMP-9 in MVECs.

calcium signaling; protein kinase C; Src; G protein-coupled receptor; nonreceptor tyrosine kinase; protein G_i; protein G_q; protein tyrosine kinase 2; microvascular endothelial cell; cardiovascular remodeling

This article has been cited by other articles:

				K. Coral, N. Angayarkanni, N. Gomathy, M. Bharathselvi, R. Pukhraj, and R. Rupak Homocysteine Levels in the Vitreous of Proliferative Diabetic Retinopathy and Rhegmatogenous Retinal Detachment: Its Modulating Role on Lysyl Oxidase Invest. Ophthalmol. Vis. Sci., August 1, 2009; 50(8): 3607 - 3612. [Abstract] [Full Text] [PDF]

				U. Sen, N. Tyagi, M. Kumar, K. S. Moshal, W. E. Rodriguez, and S. C. Tyagi Cystathionine- -synthase gene transfer and 3-deazaadenosine ameliorate inflammatory response in endothelial cells Am J Physiol Cell Physiol, December 1, 2007; 293(6): C1779 - C1787. [Abstract] [Full Text] [PDF]

				K. S. Moshal, M. Singh, U. Sen, D. S. E. Rosenberger, B. Henderson, N. Tyagi, H. Zhang, and S. C. Tyagi Homocysteine-mediated activation and mitochondrial translocation of calpain regulates MMP-9 in MVEC Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2825 - H2835. [Abstract] [Full Text] [PDF]