Apelin and its Receptor APJ in Human Aortic Valve Stenosis

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-AT(1)-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 (AT(1) and AT(2)) 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. AT(2)-receptor mRNA levels were 90% (p <0.001) lower in stenotic valves. In contrast, the gene expression of AT(1)-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.