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CLINICAL STUDY

Nitroglycerin upregulates matrix metalloproteinase expression by human macrophages

Alison K. Death, PhD^*, Shirley Nakhla, BSc, Kristine C. Y. McGrath, BSc (Hons)^*, Sally Martell, BSc (Hons), Dennis K. Yue, MBBS, PhD, FRACP^*, Wendy Jessup, PhD and David S. Celermajer, MBBS, PhD, FRACP^*,*

^* Department of Medicine, University of Sydney, Sydney, Australia
Heart Research Institute, Camperdown, Australia
Departments of Endocrinology, Camperdown, Australia
Cardiology, Royal Prince Alfred Hospital, Camperdown, Australia

Manuscript received July 11, 2001; revised manuscript received March 11, 2002, accepted April 1, 2002.

^* Reprint requests and correspondence: Prof. David S. Celermajer, Department of Cardiology, Royal Prince Alfred Hospital, Missendon Road, Camperdown Sydney, NSW 2050, Australia.

OBJECTIVES: This study aimed to determine whether nitroglycerin (NTG) treatment affects matrix metalloproteinase (MMP) gene expression and activities in human macrophages.

BACKGROUND: Nitroglycerin is one of the most frequently used therapeutic agents for the symptomatic relief of stable or unstable coronary artery disease; however, its effects on vascular biology are poorly characterized. Despite its powerful vasodilator activity, NTG has not been shown to improve outcomes in coronary disease. We now describe evidence that NTG has potentially pro-inflammatory effects in human monocyte-derived macrophages (MDMs).

METHODS: Human monocytes were isolated from whole blood by elutriation and allowed to differentiate into macrophages over eight to 10 days. The MDMs were then treated for 4 or 24 h with control media, pharmacologically relevant doses of NTG or other nitric oxide donors. Matrix metalloproteinase activity was measured by zymography, protein levels measured by enzyme-linked immunosorbent assay and messenger ribonucleic acid (mRNA) levels were quantified by competitive reverse transcription-polymerase chain reaction.

RESULTS: The major MMP expressed by MDMs was MMP-9. Nitroglycerin treatment stimulated a dose-dependent increase in MMP-9 mRNA levels (NTG 200 pmol: 193 ± 6% and NTG 2,000 pmol: 372 ± 9% compared to controls, p < 0.005) and MMP-9 activity (NTG 200: 142 ± 5.5% and NTG 2,000: 167 ± 11% compared to controls, p < 0.005). Nitroglycerin 2,000 pmol also increased MMP-2 and MMP-7 mRNA levels to 187 ± 8% and 183 ± 21% of control values, respectively (p < 0.05). Furthermore, tissue inhibitor of metalloproteinase (TIMP)-1 (the major tissue inhibitor of MMPs) mRNA and protein levels were decreased in NTG 2,000 pmol-treated MDMs compared with control cells (mRNA: 67 ± 7%, p < 0.005; protein: 45 ± 5%, p < 0.005).

CONCLUSIONS: Nitroglycerin in pharmacologically relevant concentrations activates MMP but represses TIMP expression in human macrophages. The subsequent imbalance in MMP/TIMP expression associated with NTG treatment could promote matrix degradation, with potentially adverse effects on plaque stability.

Abbreviations and Acronyms   AP-1   activator protein-1   APMA   p-aminophenyl mercuric acetate   CAD   coronary artery disease   GLY   glycerol   MDM   monocyte-derived macrophage   MMP   metalloproteinase   mRNA   messenger ribonucleic acid   NF-B   nuclear factor-kappa B   NO   nitric oxide   NTG   nitroglycerin   RNA   ribonucleic acid   ROS   reactive oxygen species   RT-PCR   reverse transcription-polymerase chain reaction   SDS-PAGE   sodium dodecyl sulfate-polyacrylamide gels   TIMP   tissue inhibitors of metalloproteinase

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