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Published on: October 15, 2010
Endothelin-1 and endothelin converting enzyme-1 in human atherosclerosis--novel targets for pharmacotherapy in
C Ihling1, B Bohrmann, H E Schaefer
1Department of Pathology, University of Freiburg, Albertsrabetae 19, 79104 Freiburg/Germany. ktechnau-ihling@ gmx.de
Insights
Chronic inflammation drives acute coronary syndromes, with active plaques showing higher levels of endothelin-1 (ET-1). This potent vasoconstrictor, regulated by endothelin converting enzyme-1 (ECE-1), is linked to plaque instability and progression.
Area of Science:
- Cardiovascular Biology
- Atherosclerosis Pathogenesis
- Inflammation Research
Background:
- Active atherosclerotic plaques, rich in macrophages, are prone to rupture, unlike stable myofibroblast-rich plaques.
- Active plaques exhibit enhanced local vasoreactivity, influenced by the vasoconstrictor endothelin-1 (ET-1).
- ET-1, produced by inflammatory cells, and its activating enzyme ECE-1, are implicated in vascular tone regulation and cell growth during atherosclerosis.
Purpose of the Study:
- To investigate the presence and activity of ECE-1 and ET-1 in various atherosclerotic plaque types.
- To correlate ET-1 levels and ECE-1 activity with the inflammatory state and progression of atherosclerosis.
- To examine ET-1 localization within human coronary plaque tissue and its association with lesion activity.
Main Methods:
- Evaluation of ECE-1 and ET-1 presence and ECE-1 activity in different plaque types.
- Immunohistochemical analysis of ET-1 in coronary plaque tissue obtained via directional coronary atherectomy.
- Semiquantitative assessment of ET-1 immunoreactivity in active versus non-active coronary lesions.
Main Results:
- ECE-1 and ET-1 are found in endothelial cells, vascular smooth muscle cells, and macrophages within plaques.
- Both ECE-1 activity and ET-1 immunoreactivity are upregulated with atherosclerosis progression, from non-inflammatory to inflammatory stages.
- Significantly higher ET-1 immunoreactivity was observed in active coronary lesions compared to non-active lesions.
Conclusions:
- Enhanced ET-1 production, facilitated by ECE-1, contributes to cell growth and vascular tone regulation in advanced and early atherosclerotic plaques.
- Increased ET-1 in active coronary lesions may play a dual role: potentially stabilizing the vessel wall post-rupture but also promoting vasospasm and disease progression.
- ET-1 is a key component associated with chronic inflammation in coronary atherosclerosis.
Abstract:
The role of chronic inflammation in the pathogenesis of the acute coronary syndromes has received increasing attention since active plaques rich in macrophages (Mphi's) are more prone to rupture whereas plaques rich in myofibroblasts are considered to be stable. Functionally, active plaques show a locally enhanced vasoreactivity. Endothelin-1 (ET-1) a potent vasoconstrictor acts in a paracrine fashion to regulate vascular tone. ET-1 is also produced by inflammatory cells suggesting a role for ET-1 in inflammation. Additionally, ET-1 is a mitogen. Endothelin converting enzyme-1 (ECE-1) activates ET-1 and may thus contribute to the regulation of vascular tone and cell growth during atherosclerosis. We evaluated the presence of ECE-1 and big ET-1/ET-1 and the activity of ECE-1 in different plaque types. Together with ET-1, ECE-1 is present in endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and Mphi's. ECE-1 activity and ET-1-immunoreactivity (IR) both are upregulated during the progression of atherosclerosis from a non-inflammatory to an inflammatory stage. Thus, enhanced production of active ET-1 may contribute to cell growth and regulation of vascular tone in advanced plaques and also in very early stages of atherosclerosis. Furthermore, we examined the presence of ET-1 in coronary plaque tissue obtained by directional coronary atherectomy. ET-1 IR localized to plaque components indicative of chronic inflammation. Semiquantitative analysis of ET-1 IR revealed significantly higher staining grades in active coronary lesions compared with nonactive lesions. The increased ET-1 content in active coronary lesions may be beneficial to the stabilization of the vessel wall after plaque rupture and disadvantageous because it may lead to vasospasm and to the progression of atherosclerosis.
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