Broad regulation of matrix and adhesion molecules in THP-1 human macrophages by nitroglycerin.
Although nitroglycerin (NTG) is effective for the acute relief in coronary ischemic diseases, its long-term benefits in mortality and morbidity have been questioned. The possibility has been raised that NTG may increase the activity of matrix metalloproteinases (MMP), which could lead to disruption and dislodging of atherosclerotic plaques. This study examined the broad effects of acute NTG exposure on the expression and activity of genes encoding MMP-9, as well as an array of ECM and adhesion molecules in THP-1 human macrophages. Gene array studies identified that while NTG exposure (100microM, 48h) did not significantly increase MMP-9 gene expression, genes encoding testican-1, integrin alpha-1, thrombospondin-3, fibronectin-1 and MMP-26 were significantly down-regulated. On the other hand, genes encoding catenin beta-1 and vascular cell-adhesion molecule-1 were up-regulated. Real-time PCR studies confirmed significant down-regulation of testican-1 gene expression, but its protein expression was not significantly altered. NTG exposure, caused a significant increase in total MMP-9 protein expression (1.96-fold) and active MMP-9 (3.7-fold) concentrations. Recombinant MMP-9 was significantly activated by NTG and its dinitrate metabolites, indicating post-translation modification of this protein by organic nitrates. These results indicate that NTG exposure could broadly affect the gene expression and activity of proteases that govern the ECM cascade, thereby potentially altering atherosclerotic plaque stability.
Krishnatry
Anu Shilpa
AS
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260-1200, USA.
Brazeau
Daniel A
DA
Fung
Ho-Leung
HL
D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D005996:Nitroglycerin / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019699:Thrombospondins / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D011509:Proteoglycans; D011994:Recombinant Proteins; C504369:SPOCK1 protein, human; D019699:Thrombospondins; D019010:Vascular Cell Adhesion Molecule-1; D051176:beta Catenin; C101863:thrombospondin 3; D020782:Matrix Metalloproteinases; D005996:Nitroglycerin