Increased production of CXCL16 in experimental and clinical heart failure: a possible role in extracellular matrix remodeling.
BACKGROUND
Inflammation has been implicated in the pathogenesis of heart failure (HF), but knowledge about the production and role of inflammatory actors remains incomplete. On the basis of its role in vascular inflammation, vascular proliferation, and matrix degradation, we hypothesized a role for the chemokine CXCL16 in the pathogenesis of myocardial remodeling and development of HF.


RESULTS
Our main findings were (1) patients with chronic HF (n=188) had increased plasma levels of CXCL16, which correlated with disease severity. (2) Left ventricular tissue from patients with end-stage HF (n=8) showed enhanced CXCL16 levels compared with nonfailing left ventricular (n=6) as assessed by Western blotting. (3) In mice with postmyocardial infarction HF, expression of CXCL16, as assessed by real-time RT-PCR, was increased in the infarcted and the noninfarcted areas of left ventricular 3 and 7 days after coronary ligation, indicating early onset of CXCL16 production. Furthermore, mice exposed to aortic banding had enhanced CXCL16 expression in left ventricular, indicating that CXCL16 expression is not related to ischemia alone. (4) In vitro, CXCL16 promoted proliferation and impaired collagen synthesis in myocardial fibroblasts, and in cardiomyocytes and myocardial fibroblasts, CXCL16 increased matrix metalloproteinase activity, primarily reflecting increased matrix metalloproteinase-2 levels. (5) By using specific inhibitors, we showed that the effect of CXCL16 on fibroblasts involved activation of Jun N-terminal kinase.


CONCLUSIONS
We show enhanced myocardial CXCL16 expression in experimental and clinical HF. The effect of CXCL16 on cardiomyocytes and fibroblasts suggests a role for CXCL16 in matrix remodeling and ultimately in the development of HF.
Dahl
Christen Peder
CP
Research Institute for Internal Medicine, Department of Cardiology, Section of Clinical Immunology and Infectious Diseases, Section of Endocrinology, and Institute for Surgical Research, Rikshospitalet University Hospital, University of Oslo, Norway.
Husberg
Cathrine
C
Gullestad
Lars
L
Waehre
Anne
A
Damås
Jan Kristian
JK
Vinge
Leif Erik
LE
Finsen
Alexandra V
AV
Ueland
Thor
T
Florholmen
Geir
G
Aakhus
Svend
S
Halvorsen
Bente
B
Aukrust
Pål
P
Oie
Erik
E
Yndestad
Arne
A
Christensen
Geir
G
D000328:Adult; D000368:Aged; D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D002478:Cells, Cultured; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6 / Q000235:genetics / Q000378:metabolism*; D019743:Chemokines, CXC / Q000097:blood / Q000378:metabolism*; D002908:Chronic Disease; D003094:Collagen / Q000096:biosynthesis; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006333:Heart Failure / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011392:Proline / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051116:Receptors, Scavenger / Q000097:blood / Q000378:metabolism*; D015854:Up-Regulation; D020257:Ventricular Remodeling
C423727:CXCL16 protein, human; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D019743:Chemokines, CXC; C498926:Cxcl16 protein, mouse; D018836:Inflammation Mediators; D012333:RNA, Messenger; D051116:Receptors, Scavenger; D003094:Collagen; D011392:Proline; D048031:JNK Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9