Fatty Acid Binding Protein 4 Is Associated with Carotid Atherosclerosis and Outcome in Patients with Acute Ischemic Stroke

David Russell,Christoph Christoph,Tuva B Dahl,James L Januzzi,Sverre Holm,Kirsten Krohg-Sørensen,Thor Ueland,Pål Aukrust,Annika E Michelsen,Dan Atar,Mona Skjelland,Bente Halvorsen,Jesper K Jensen,Ole Petter Clausen,Ståle H Nymo

doi:10.1371/journal.pone.0028785

Abstract

Background and PurposeFatty acid binding protein 4 (FABP4) has been shown to play an important role in macrophage cholesterol trafficking and associated inflammation. To further elucidate the role of FABP4 in atherogenesis in humans, we examined the regulation of FABP4 in carotid atherosclerosis and ischemic stroke.MethodsWe examined plasma FABP4 levels in asymptomatic (n = 28) and symptomatic (n = 31) patients with carotid atherosclerosis, as well as in 202 subjects with acute ischemic stroke. In a subgroup of patients we also analysed the expression of FABP4 within the atherosclerotic lesion. In addition, we investigated the ability of different stimuli with relevance to atherosclerosis to regulate FABP4 expression in monocytes/macrophages.ResultsFABP4 levels were higher in patients with carotid atherosclerosis, both systemically and within the atherosclerotic lesion, with particular high mRNA levels in carotid plaques from patients with the most recent symptoms. Immunostaining of carotid plaques localized FABP4 to macrophages, while activated platelets and oxidized LDL were potent stimuli for FABP4 expression in monocytes/macrophages in vitro. When measured at the time of acute ischemic stroke, high plasma levels of FABP4 were significantly associated with total and cardiovascular mortality during follow-up, although we did not find that addition of FABP4 to the fully adjusted multivariate model had an effect on the prognostic discrimination for all-cause mortality as assessed by c-statistics.ConclusionsFABP4 is linked to atherogenesis, plaque instability and adverse outcome in patients with carotid atherosclerosis and acute ischemic stroke.

Highlights

Atherosclerosis is a chronic disease characterized by two fundamental hallmarks: lipid accumulation and inflammation. [1] The interaction between these two processes defines the principal pathogenesis of atherosclerosis, and distinguishes it from other chronic inflammatory disorders
While originally described as an adipose tissue protein, [4,5] recent work has shown a pivotal role for Fatty acid binding protein 4 (FABP4) in macrophages in relation to cholesterol trafficking and inflammation. [6,7] In line with this, total or macrophage-specific FABP4-deficiency has been shown to protect against atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice, [8] and FABP4 has been suggested as a potential drug target in diseases like diabetes and atherosclerosis
To further elucidate the role of FABP4 in atherogenesis in humans, we examined the regulation of FABP4 in atherosclerosis and ischemic stroke in three different ways: (i) In a cross-sectional study of patients with symptomatic and asymptomatic carotid plaques we analyzed FABP4 levels in plasma and plaque samples. (ii) In an in vitro study, we examined the regulation of FABP4 in monocytes/macrophages. (iii) In a separate sub-study, we examined the association between plasma levels of FABP4 in acute ischemic stroke and mortality during long-term follow-up

Summary

Introduction

Atherosclerosis is a chronic disease characterized by two fundamental hallmarks: lipid accumulation and inflammation. [1] The interaction between these two processes defines the principal pathogenesis of atherosclerosis, and distinguishes it from other chronic inflammatory disorders. While originally described as an adipose tissue protein, [4,5] recent work has shown a pivotal role for FABP4 in macrophages in relation to cholesterol trafficking and inflammation. To further elucidate the role of FABP4 in atherogenesis in humans, we examined the regulation of FABP4 in atherosclerosis and ischemic stroke in three different ways: (i) In a cross-sectional study of patients with symptomatic and asymptomatic carotid plaques we analyzed FABP4 levels in plasma and plaque samples. Fatty acid binding protein 4 (FABP4) has been shown to play an important role in macrophage cholesterol trafficking and associated inflammation. To further elucidate the role of FABP4 in atherogenesis in humans, we examined the regulation of FABP4 in carotid atherosclerosis and ischemic stroke

Methods

Results

Conclusion