on October 27, 2005
Published online before print October 27, 2005, doi: 10.1161/01.ATV.0000193567.88685.f4
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Submitted on December 9, 2004
Accepted on September 26, 2005
Expression of Neutrophil Gelatinase-Associated Lipocalin in Atherosclerosis and Myocardial Infarction
Anne-Louise Hemdahl ;
From the Center for Molecular Medicine and Department of Medicine (A.-L.H., A.G., G.K.H.), Karolinska Hospital, Stockholm, Sweden; the Department of Physiology and Pharmacology (A.-L.H., P.T.) and King Gustaf V Research Institute, Department of Medicine, Karolinska Hospital M1 (C.Z., P.E.), Karolinska Institute, Stockholm, Sweden; the Division for Vascular Surgery (U.H.), Department of Surgical Sciences, Karolinska University Hospital, Stockholm, Sweden; and the Cardiac Catheterization Laboratory 2014 (J.K.), The Heart Centre, Rigshospitalet, Copenhagen, Denmark.
* To whom correspondence should be addressed. E-mail: Goran.Hansson{at}cmm.ki.se.
Objective--Neutrophil gelatinase-associated lipocalin (NGAL) modulates the activity of matrix metalloproteinase (MMP) 9, an important mediator of vascular remodeling and plaque instability in atherosclerosis. This study aimed to analyze the expression of NGAL in atherosclerotic plaques and myocardial infarction (MI).
Methods and Results--Atherosclerotic apolipoprotein E (apoE)-/- x low-density lipoprotein receptor (LDLR)-/- and C57BL/6J control mice were exposed to brief hypoxic stress (10 minutes of 10% oxygen). Expression of the mouse NGAL homolog (24p3) and MMP-9 was analyzed 48 hours later by quantitative RT-PCR, immunohistochemistry, and zymography. Hypoxic stress increased NGAL/24p3 mRNA in the cardiac vasculature. NGAL/24p3 was also increased in atherosclerotic plaques of apolipoprotein E-/- x LDLR-/- mice compared with C57BL/6J mice. Mice developing MI exhibited the highest plaque mRNA expression of NGAL/24p3 and MMP-9. Zymography revealed strong proteolytic activity in areas rich in 24p3 and MMP-9 protein. Immunohistochemistry performed on human carotid endarterectomy specimens and control tissue from the internal mammary artery showed colocalization of MMP-9 and NGAL with macrophages in the atherosclerotic plaques.
Conclusions--NGAL/24p3 is increased in atherosclerotic plaques and MI. Colocalization with MMP-9 in areas with high-proteolytic activity suggests a role for NGAL/24p3 in modulating the MMP-9-mediated remodeling of plaques and infarcted hearts.
Key words: atherosclerosis • myocardial infarction • ischemia • hypoxia • matrix metalloproteinase • remodeling
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