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

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Su, Y. Articles by Block, E. R. Search for Related Content PubMed Articles by Su, Y. Articles by Block, E. R.

Concentration-dependent Effects of Nitric Oxide on Angiogenesis of Lung Microvascular Endothelial Cells

Role of Calpain Nitrosylation

University of Florida and Malcom Randall VA Medical Center, Gainesville, Florida

Correspondence and requests for reprints should be addressed to Yunchao Su, M.D., Ph.D., Dept. of Medicine, University of Florida, 1600 SW Archer Road, Gainesville, FL 32610. E-mail: ysu{at}ufl.edu

Alteration of angiogenesis plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). In COPD, lung cells, including pulmonary microvascular endothelial cells, are exposed to varying amounts of nitric oxide (NO) that is endogenous (i.e., constitutive eNOS or secondary to induction of iNOS in tobacco smoke–activated alveolar macrophages) and/or exogenous (i.e., from tobacco smoke). Calpains, a family of calcium-sensitive neutral endopeptidase, mediate cellular motility in endothelial angiogenesis. In this study, we investigated the effects of different concentrations of NO on angiogenesis of lung microvascular endothelial cells (PMEC). Human PMEC were incubated with NO donors, NOC-18 and s-nitroso-N-acetyl-D, L-penicillamine (SNAP), in concentrations of 10–700 µM and 1–400 µM, respectively, after which endothelial monolayer wound repair, tube formation on matrigel, calpain activity, and protein nitrosylation of calpains and actin were measured. Incubation of PMEC with NOC-18 in concentrations of 5–50 µM and SNAP in concentrations of 1–10 µM caused significant increases in endothelial monolayer wound repair and tube formation on matrigel. The activity and protein nitrosylation of calpain did not change. Incubation of PMEC with NOC-18 in concentrations of 400–700 µM and SNAP in concentrations of 50–400 µM caused decreases in endothelial monolayer wound repair and tube formation and in calpain activity and an increase in the protein nitrosylation of calpain-1. The protein nitrosylation of actin did not change. A specific inhibitor of the soluble guanylyl cyclase, 1H-[1,2,4] oxadiazolo [4,3,-a] quinoxalin-1-one (ODQ), prevented the pro-angiogenic but not the anti-angiogenic effect of NOC-18 and SNAP. These results indicate that NO in lower concentrations enhances angiogenesis via a cGMP-dependent mechanism, and that higher amounts of NO inhibit angiogenesis via cGMP-independent mechanisms. Inhibition of calpain-1 due to protein nitrosylation might be involved in the anti-angiogenic effect of NO. Alterations in lung angiogenesis may affect the inflammatory response in the lungs of cigarette smokers and contribute to the altered vascular remodeling observed in the lungs of patients with cigarette smoke–related COPD.

FOOTNOTES

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form March 17, 2006; accepted in final form March 28, 2006)

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Su, Y. Articles by Block, E. R. Search for Related Content PubMed Articles by Su, Y. Articles by Block, E. R.