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Apelin and its receptor APJ in human aortic valve stenosis
Tuomas Peltonen1, Juha Näpänkangas, Olli Vuolteenaho
1Department of Pharmacology and Toxicology, University of Oulu, Biocenter Oulu, Finland.
Insights
Aortic valve stenosis shows increased apelin-APJ signaling, suggesting a new therapeutic target for calcified aortic valve disease by inhibiting key disease processes.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Pathology
Background:
- Aortic valve stenosis (AS) shares characteristics with atherosclerosis.
- The apelin-APJ system's role in AS is currently unknown.
- Apelin-APJ signaling may oppose the angiotensin II-AT1-receptor pathway.
Purpose of the Study:
- To investigate the role of the apelin-APJ signaling pathway in aortic valve stenosis.
- To compare expression of apelin, APJ, and angiotensin II receptors in normal and diseased aortic valves.
Main Methods:
- Analyzed aortic valve tissue from patients with normal valves, aortic regurgitation (AR), AR with sclerosis, and AS.
- Utilized reverse-transcriptase polymerase chain reaction (RT-PCR) for gene expression analysis.
- Employed immunohistochemistry to determine protein localization.
Main Results:
- Apelin and APJ receptor gene expression were significantly upregulated in stenotic valves.
- APJ receptor mRNA levels were also higher in valves with AR and sclerosis.
- AT2 receptor mRNA levels were significantly lower in stenotic valves, while AT1 receptor expression did not differ.
Conclusions:
- Aortic valve stenosis is associated with increased apelin-APJ signaling.
- This pathway represents a potential novel drug target for calcified aortic valve disease.
- Targeting this pathway could suppress disease processes like chemotaxis, angiogenesis, and osteoblast activity.
Background And Aim Of The Study:
Aortic valve stenosis (AS) is an actively regulated pathobiological process that shows some hallmarks of atherosclerosis. Apelin and its receptor, APJ, are highly expressed in the heart, and the proposed effects of the apelin-APJ system are opposite to those of the angiotensin II-AT1-receptor pathway. The role of the apelin-APJ signaling pathway in calcified aortic valve disease is unknown.
Methods:
The study involved the characterization and comparison of expression of apelin and APJ as well as angiotensin II receptors (AT1 and AT2) in the aortic valves of patients with normal valves (n = 6), aortic regurgitation (n = 9 AR), regurgitation and fibrosis/mild sclerosis (n = 14), and AS (n = 25).
Results:
By employing the reverse-transcriptase polymerase chain reaction (RT-PCR), the gene expression of apelin (3.63-fold, p = 0.001) and the APJ receptor (2.70-fold, p = 0.01) were shown to be significantly up-regulated in stenotic valves when compared to controls. In addition, APJ receptor mRNA levels were higher (2.9-fold, p = 0.010) in the AR + sclerosis group when compared to controls. Using immunohistochemistry, apelin was shown to be localized in stenotic aortic valves to the valvular endothelial layer of the aortic valve, to vascular endothelial cells in neovessels, and to fibroblasts and macrophages adjacent to vessels in the stromal area. AT2-receptor mRNA levels were 90% (p < 0.001) lower in stenotic valves. In contrast, the gene expression of AT1-receptors did not differ significantly among the groups.
Conclusion:
Aortic valve stenosis is characterized by an up-regulation of the apelin-APJ signaling pathway, revealing a possible novel target for drug discovery in calcified aortic valve disease by suppressing chemotaxis, angiogenesis and osteoblast activity, all of which are well-documented phenomena in the disease process.
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