Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction.
BACKGROUND
Apelin is among the most potent stimulators of cardiac contractility known. However, no physiological or pathological role for apelin-angiotensin receptor-like 1 (APJ) signaling has ever been described.


RESULTS
We performed transcriptional profiling using a spotted cDNA microarray with 12 814 unique clones on paired samples of left ventricle obtained before and after placement of a left ventricular assist device in 11 patients. The significance analysis of microarrays and a novel rank consistency score designed to exploit the paired structure of the data confirmed that natriuretic peptides were among the most significantly downregulated genes after offloading. The most significantly upregulated gene was the G-protein-coupled receptor APJ, the specific receptor for apelin. We demonstrate here using immunoassay and immunohistochemical techniques that apelin is localized primarily in the endothelium of the coronary arteries and is found at a higher concentration in cardiac tissue after mechanical offloading. These findings imply an important paracrine signaling pathway in the heart. We additionally extend the clinical significance of this work by reporting for the first time circulating human apelin levels and demonstrating increases in the plasma level of apelin in patients with left ventricular dysfunction.


CONCLUSIONS
The apelin-APJ signaling pathway emerges as an important novel mediator of cardiovascular control.
Chen
Mary M
MM
Donald W. Reynolds Cardiovascular Research Center, Division of Cardiovascular Medicine, Falk CVRC, Stanford University, 300 Pasteur Dr, Stanford, Calif 94305, USA.
Ashley
Euan A
EA
Deng
David X F
DX
Tsalenko
Anya
A
Deng
Alicia
A
Tabibiazar
Raymond
R
Ben-Dor
Amir
A
Fenster
Brett
B
Yang
Eugene
E
King
Jennifer Y
JY
Fowler
Michael
M
Robbins
Robert
R
Johnson
Frances L
FL
Bruhn
Laurakay
L
McDonagh
Theresa
T
Dargie
Henry
H
Yakhini
Zohar
Z
Tsao
Philip S
PS
Quertermous
Thomas
T
D000293:Adolescent; D000328:Adult; D000073861:Apelin; D000075244:Apelin Receptors; D015415:Biomarkers / Q000032:analysis; D002352:Carrier Proteins / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D016000:Cluster Analysis; D003331:Coronary Vessels / Q000378:metabolism; D018450:Disease Progression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology* / Q000601:surgery; D006353:Heart-Assist Devices; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019899:Paracrine Communication; D011237:Predictive Value of Tests; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000503:physiopathology / Q000601:surgery
C115436:APLN protein, human; C104575:APLNR protein, human; D000073861:Apelin; D000075244:Apelin Receptors; D015415:Biomarkers; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled