Published online before print December 24, 2007, doi: 10.1161/HYPERTENSIONAHA.107.103739
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(Hypertension. 2008;51:e13.)
© 2008 American Heart Association, Inc.
Letters to the Editor |
Lysyl Oxidase Inhibition Is Responsible for the Vascular Elastic Fiber Phenotype
Leibniz-Institute for Arteriosclerosis Research, Department of Thoracic and Cardiovascular Surgery, Department of Cardiology and Angiology, University Hospital Münster, Münster, Germany
Department of Thoracic and Cardiovascular Surgery, University Hospital Münster, Münster, Germany
Leibniz-Institute for Arteriosclerosis Research, Department of Thoracic and Cardiovascular Surgery, University Hospital Münster, Münster, Germany
In the July issue of Hypertension, Mercier et al1 demonstrated a rat model in which the structural vascular phenotype is modified in response to amine oxidase inhibition by semicarbazide. Under these conditions, the elastic lamellae presented globular masses along their periphery, and focal disorganization was observed in the ascending aorta. Immunoconfocal microscopy demonstrated branching of elastic lamellae and a sparse hairy aspect of some elastic fibers after amine oxidase inhibition. Because the above-described abnormalities are not found in semicarbazide-sensitive amine oxidase–deficient mice, the authors conclude that these effects cannot be attributable to amine oxidase inhibition. However, semicarbazide-mediated inhibition of amino oxidase was associated with decreased lysyl oxidase (LOX) activity. From their data, the authors assume that this LOX inhibition might be responsible for the major part of the vascular phenotype of semicarbazide-treated rats.
Our studies on the regulation of vessel wall integrity and plaque stability by mediators of inflammation, ie, the proinflammatory cytokine granulocyte macrophage colony–stimulating factor (GM-CSF),2,3 strongly support the hypothesis of Mercier et al1 that the observed elastic phenotype is related to LOX inhibition. As recently shown by our group, GM-CSF(–/–) mice show abnormalities of the elastic system with striking similarity to those described in the present article for rats after semicarbazide treatment, ie, amorphous matrix lining the surface of the elastic lamellae, elastic fiber hypertrophy as we classified it or as stated by Mercier et al,1 a hairy aspect of some elastic fibers.3 Moreover, ultrastructural analysis revealed that GM-CSF(–/–) mice show also collagen fiber abnormalities: disorganized collagen bundles and abnormal collagen fibers with widely varying diameters.2 Taken together, our data pointed to compromised fiber cross-linkage. Indeed, expression of LOX and of the LOX-activator bone morphogenic protein was reduced in the aorta of GM-CSF(–/–) mice. Moreover, treatment of vascular smooth muscle cells with GM-CSF stimulated the expression of LOX.3
Thus, the observed changes in the elastic fiber system of the aorta of semicarbazide-treated rats are highly compatible with the elastin phenotype of GM-CSF(–/–) mice. Furthermore, the elastic phenotypes of both models are in line with the phenotype of LOX-deficient mice,4 suggesting that the molecular mechanism underlying the formation of abnormal elastic lamellae in both animal models is the compromised elastic fiber cross-linkage as a result of reduced LOX activity or expression.
Because both semicarbazide-sensitive amine oxidase and inflammatory mediators are increased in processes of vascular inflammation and because semicarbazide-sensitive amine oxidase inhibition is associated with a downregulation of inflammatory mediators,5 the relation between ECM-modulating inflammatory mediators, such as GM-CSF and semicarbazide-sensitive amine oxidase, should be addressed.
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Acknowledgments |
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Sources of Funding
This work was supported by the Innovative Medizinische Forschung program and the Heart Center, Münster.
Disclosures
None.
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References |
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 Top References |
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1. Mercier N, El Hadri K, Osborne-Pellegrin M, Nehme J, Perret C, Labat C, Regnault V, Lamaziere JM, Challande P, Lacolley P, Feve B. Modifications of arterial phenotype in response to amine oxidase inhibition by emicarbazide. Hypertension. 2007; 50: 234–241.
2. Plenz G, Eschert H, Beissert S, Arps V, Sindermann J, Robenek H, Völker W. Alterations in the vascular extracellular matrix of granulocyte macrophage colony stimulating factor (GM-CSF)–deficient mice. FASEB J. 2003; 17: 1451–1457.
3. Weissen-Plenz G, Eschert H, Volker W, Sindermann JR, Beissert S, Robenek H, Scheld HH, Breithardt G. Granulocyte macrophage colony-stimulating factor deficiency affects vascular elastin production and integrity of elastic lamellae. J Vasc Res. 2007; 45: 103–110.[Medline] [Order article via Infotrieve]
4. Maki JM, Rasanen J, Tikkanen H, Sormunen R, Makikallio K, Kivirikko KI, Soininen R. Inactivation of the lysyl oxidase gene Lox leads to aortic aneurysms, cardiovascular dysfunction, and perinatal death in mice. Circulation. 2002; 106: 2503–2509.
5. Salter-Cid LM, Wang E, O’Rourke AM, Miller A, Gao H, Huang L, Garcia A, Linnik MD. Anti-inflammatory effects of inhibiting the amine oxidase activity of semicarbazide-sensitive amine oxidase. J Pharmacol Exp Ther. 2005; 315: 553–562.
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  N. Mercier, K. El Hadri, M. Osborne-Pellegrin, J. Nehme, C. Perret, C. Labat, V. Regnault, J.-M. D. Lamaziere, P. Challande, B. Feve, et al. Response to Lysyl Oxidase Inhibition Is Responsible for the Vascular Elastic Fiber Phenotype Hypertension, February 1, 2008; 51(2): e14 - e14. [Full Text] [PDF]
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