Published Online
on September 22, 2009

A more recent version of this article appeared on November 1, 2009

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Original Article

Increased Production of CXCL16 in Experimental and Clinical Heart Failure: A Possible Role in Extracellular Matrix Remodeling

Christen Peder Dahl¹; Cathrine Husberg²; Lars Gullestad¹; Anne Wæhre²; Jan Kristian Damås¹; Leif Erik Vinge¹; Alexandra Finsen³; Thor Ueland¹; Geir Florholmen²; Svend Aakhus¹; Bente Halvorsen¹; Pål Aukrust^1,4; Erik Øie¹; Arne Yndestad¹ and Geir Christensen²

¹ Rikshospitalet University Hospital, University of Oslo, Oslo, Norway;
² Ullevål University Hospital and University of Oslo, Oslo, Norway;
³ Rikshospitalet University Hospital; Ullevål University Hospital ; Uni. of Oslo, Oslo, Norway

^* Corresponding author; email: pal.aukrust{at}rikshospitalet.no

Background—Inflammation has been implicated in the pathogenesis of heart failure (HF), but knowledge about production and role of inflammatory actors remain incomplete. Based on 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.

Methods and Results—Our main findings were: (i) Patients with chronic HF (n=188) had raised plasma levels of CXCL16, which correlated with disease severity. (ii) Left ventricular (LV) tissue from patients with end-stage HF (n=8) showed enhanced CXCL16 levels compared to non-failing LV (n=6) as assessed by Western blotting. (iii) In mice with post-myocardial infarction HF, expression of CXCL16, as assessed by real-time RT-PCR, was increased in the infarcted and the non-infarcted areas of LV 3 and 7 days after coronary ligation, indicating early onset of CXCL16 production. Also, mice exposed to aortic banding had enhanced CXCL16 expression in LV, indicating that CXCL16 expression is not only related to ischemia. (iv) In vitro, CXCL16 promoted proliferation and impaired collagen synthesis in myocardial fibroblasts, and in cardiomyocytes and myocardial fibroblasts, CXCL16 increased MMP activity, primarily reflecting increased MMP-2 levels. (v) Using specific inhibitors, we showed that the effect of CXCL16 on fibroblasts involved activation of Jun N-terminal kinase.

Conclusion—We show enhanced myocardial CXCL16 expression in experimental and clinical HF. The effect of CXCL16 on cardiomyocytes and fibroblasts suggest a role for CXCL16 in matrix remodeling and ultimately also in the development of HF.

Key Words: heart failure • inflammation • metalloproteinases • remodeling • CXCL16