VAP-1, Eotaxin3 and MIG as potential atherosclerotic triggers of severe calcified and stenotic human aortic valves: effects of statins.
Sclerotic calcification of the aortic valve is a common disease in advanced age. Its pathophysiology is unclear. However, pathobiological similarities to atherosclerosis have been shown in several studies. The current study assesses gene profiling of severe calcified stenotic human aortic valves identifying transforming growth factor (TGF)-beta, Eotaxin3, vascular adhesion protein-1 (VAP-1) and monokine induced by interferon-gamma (MIG) as potential atherosclerotic target genes in severe calcified and stenotic aortic valves, and analyzes the effects of statins on their expression as part of an anti-inflammatory treatment strategy. We collected human severe calcified and stenotic aortic valves with (CSAV+) or without (CSAV-) statin pre-treatment prior to valve replacement and investigated gene profiling by using micro-array technique and real-time PCR for the TGF-beta, Eotaxin3, VAP-1 and MIG expression. In comparison to atherosclerotic plaques of carotid arteries, immunohistochemical staining was investigated. Results were contrasted to human normal non-calcified aortic valves as controls (C). As compared to C, TGF-beta, Eotaxin3, MIG or VAP-1 was significantly upregulated in CSAV-. In CSAV+ no significant change in gene expression was found for Eotaxin3 and MIG. In contrast, VAP-1 and TGF-beta were still upregulated. Corresponding gene expression was confirmed on atherosclerotic plaque formations of carotid arteries. Monocyte/Macrophage infiltration (presence of CD68) on aortic valves (CSAV+, CSAV-, or C) confirmed inflammatory nature of the disease. Our data support further evidence for atherosclerotic inflammation as a trigger for sclerosis in end-stage calcified stenotic aortic valves by showing upregulation of gene expression for TGF-beta, VAP-1, MIG and Eotaxin3, which is only partially inhibited by previous statin therapy. Potent benefits of statin treatment on early stages of valve disease are still propagated.
Anger
Thomas
T
Department of Cardiology, Friedrich-Alexander University Erlangen, Germany. th_anger@arcor.de
Pohle
Falk K
FK
Kandler
Lukas
L
Barthel
Thomas
T
Ensminger
Stephan M
SM
Fischlein
Theodor
T
Weyand
Michael
M
Stumpf
Christian
C
Daniel
Werner G
WG
Garlichs
Christoph D
CD
D006631:Amine Oxidase (Copper-Containing) / Q000235:genetics / Q000378:metabolism*; D001021:Aortic Valve / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D002114:Calcinosis; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D000075906:Chemokine CCL26; D054370:Chemokine CXCL9 / Q000235:genetics / Q000378:metabolism*; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D019918:Heart Valve Prosthesis Implantation; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism*; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D016212:Transforming Growth Factor beta / Q000378:metabolism
C120429:CCL26 protein, human; C080810:CXCL9 protein, human; D015815:Cell Adhesion Molecules; D000075906:Chemokine CCL26; D054370:Chemokine CXCL9; D019742:Chemokines, CC; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016212:Transforming Growth Factor beta; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing)