Apelin and its receptor APJ in human aortic valve stenosis.
OBJECTIVE
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.


CONCLUSIONS
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.
Peltonen
Tuomas
T
Department of Pharmacology and Toxicology, University of Oulu, Biocenter Oulu, Finland.
Näpänkangas
Juha
J
Vuolteenaho
Olli
O
Ohtonen
Pasi
P
Soini
Ylermi
Y
Juvonen
Tatu
T
Satta
Jari
J
Ruskoaho
Heikki
H
Taskinen
Panu
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001021:Aortic Valve / Q000378:metabolism* / Q000473:pathology; D001024:Aortic Valve Stenosis / Q000378:metabolism* / Q000473:pathology; D000073861:Apelin; D000075244:Apelin Receptors; D002114:Calcinosis / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D015536:Down-Regulation; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D055815:Young Adult
C115436:APLN protein, human; C104575:APLNR protein, human; D000073861:Apelin; D000075244:Apelin Receptors; D036341:Intercellular Signaling Peptides and Proteins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D043562:Receptors, G-Protein-Coupled