Myocardial expression of CC- and CXC-chemokines and their receptors in human end-stage heart failure.
OBJECTIVE
Chemokines regulate several biological processes, such as chemotaxis, collagen turnover, angiogenesis and apoptosis. Based on the persistent immune activation with elevated circulating levels of chemokines in patients with congestive heart failure (CHF), we have hypothesised a pathogenic role for chemokines in the development of CHF. The objective of this study was to examine mRNA levels and cellular localisation of chemokines and chemokine receptors in human CHF.


METHODS
We examined explanted hearts from ten patients with end-stage heart failure (all chambers) and in ten organ donors using an RNase protection assays and immunohistochemical techniques.


RESULTS
Our main findings were: (i) expression of eight chemokine and nine chemokine receptor genes in both failing and nonfailing myocardium, (ii) particularly high mRNA levels of monocyte chemoattractant protein (MCP)-1 and CXC-chemokine receptor 4 (CXCR4), in both chronic failing and nonfailing myocardium, (iii) decreased mRNA levels of MCP-1 and interleukin (IL)-8 in the failing left ventricles compared to failing left atria, (iv) decreased chemokine (e.g., MCP-1 and IL-8) and increased chemokine receptor (e.g., CCR2, CXCR1) mRNA levels in failing left ventricles and failing left atria compared to corresponding chambers in the nonfailing hearts and (v) immunolocalisation of MCP-1, IL-8 and CXCR4 to cardiomyocytes.


CONCLUSIONS
The present study demonstrates for the first time chemokine and chemokine receptor gene expression and protein localisation in the human myocardium, introducing a new family of mediators with potentially important effects on the myocardium. The observation of chemokine dysregulation in human end-stage heart failure may represent a previously unknown mechanism involved in progression of chronic heart failure.
Damås
J K
JK
Department of Cardiology, Division of Heart and Lung Diseases, The National Hospital, Oslo, Norway. j.k.damas@klinmed.uio.no
Eiken
H G
HG
Oie
E
E
Bjerkeli
V
V
Yndestad
A
A
Ueland
T
T
Tonnessen
T
T
Geiran
O R
OR
Aass
H
H
Simonsen
S
S
Christensen
G
G
Froland
S S
SS
Attramadal
H
H
Gullestad
L
L
Aukrust
P
P
D000328:Adult; D000704:Analysis of Variance; D002311:Cardiomyopathy, Dilated / Q000378:metabolism; D016022:Case-Control Studies; D019742:Chemokines, CC / Q000032:analysis* / Q000235:genetics; D019743:Chemokines, CXC / Q000032:analysis* / Q000235:genetics; D003327:Coronary Disease / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006333:Heart Failure / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000737:chemistry*; D012333:RNA, Messenger / Q000032:analysis; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D054398:Receptors, CCR4; D019713:Receptors, CCR5 / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics; D019707:Receptors, Chemokine / Q000032:analysis* / Q000235:genetics; D023062:Receptors, Interleukin-8A / Q000235:genetics
C515300:CCR1 protein, human; C515334:CCR2 protein, human; C515354:CCR4 protein, human; D019742:Chemokines, CC; D019743:Chemokines, CXC; D012333:RNA, Messenger; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D054398:Receptors, CCR4; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D023062:Receptors, Interleukin-8A