Fatty Acid-binding Protein 4, a Point of Convergence for Angiogenic and Metabolic Signaling Pathways in Endothelial Cells

Harjes, Ulrike; Bridges, Esther; McIntyre, Alan; Fielding, Barbara A.; Harris, Adrian L.

doi:10.1074/jbc.m114.576512

Cited by 81 publications

(59 citation statements)

References 28 publications

(35 reference statements)

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“…We suggest a potential role of FABP4 by inflammatory proteins in the generation of the atherosclerotic lesions. The findings of the current study are consistent with those of Tsukamoto et al and Hellings et al who found that macrophage infiltration and lipid core size are major risk fatctors for developing atherosclerotic lesions [2,[23][24][25].…”

Section: Association Of Fabp4 Enhanced Expression To Atherosclerosissupporting

confidence: 82%

“…Accumulation of lipids and inflammatory cells and production changes in extracellular matrix by the vascular smooth muscle cells (VSMC) participate in the formation of advanced lesions. The inflammatory response also determines plaque composition and, as a result, strongly contributes to the occurrence of plaque complications that are responsible for clinically severe acute ischemic syndromes [2,[6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…Atherosclerosis and its sequelae, including heart disease and stroke, are a major cause of morbidity and the leading cause of mortality in the world, and their incidence continues to rise worldwide [1][2][3][4]. Atherosclerosis has been recognized as an inflammatory disease of the arterial wall [5].…”

Section: Introductionmentioning

confidence: 99%

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FABP4 Expression as Biomarker of Atheroma Development: A Mini-Review

Ayari¹

2015

J Mol Biomark Diagn

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Atherosclerosis has been recognized as an inflammatory disease of the arterial wall. On the other hand, several studies in humans have linked Fatty acid binding protein 4 (FABP4) to coronary artery disease and its risk factors. In the literature, many experimental studies have provided strong evidence for the importance of FABP4 in the pathogenesis of cardiovascular disease. In a recent work, we proposed a potential role of FABP4 by inflammatory proteins in the generation of the atherosclerotic lesions. In conclusion, many results indicate that FABP4 is a key factor connecting vascular and cellular lipid accumulation to inflammation.

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Section: Association Of Fabp4 Enhanced Expression To Atherosclerosissupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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FABP4 Expression as Biomarker of Atheroma Development: A Mini-Review

Ayari¹

2015

J Mol Biomark Diagn

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“…23 Using a protein array and EC exposed to high glucose or latent heparanase, we observed secretion of VEGF into the culture medium ( Figure 2A, circle). Given a recent unanticipated function of VEGF in regulating EC FA transport, 24 we incubated EC with recombinant VEGF and discovered an induction of GPIHBP1 mRNA ( Figure 2B, left) and protein ( Figure 2B, right) expression within 24 hours. This increased EC GPIHBP1 in response to VEGF was predominantly membrane bound ( Figure 2C).…”

Section: Effect Of Heparanase On Gpihbp1 Expression Is Associated Witmentioning

confidence: 99%

Cardiomyocyte VEGF Regulates Endothelial Cell GPIHBP1 to Relocate Lipoprotein Lipase to the Coronary Lumen During Diabetes Mellitus

Chiu

Wan

Lal

et al. 2016

ATVB

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Objective— Lipoprotein lipase (LPL)–mediated triglyceride hydrolysis is the major source of fatty acid for cardiac energy. LPL, synthesized in cardiomyocytes, is translocated across endothelial cells (EC) by its transporter glycosylphosphatidylinositol-anchored high-density lipoprotein–binding protein 1 (GPIHBP1). Previously, we have reported an augmentation in coronary LPL, which was linked to an increased expression of GPIHBP1 following moderate diabetes mellitus. We examined the potential mechanism by which hyperglycemia amplifies GPIHBP1. Approach and Results— Exposure of rat aortic EC to high glucose induced GPIHBP1 expression and amplified LPL shuttling across these cells. This effect coincided with an elevated secretion of heparanase. Incubation of EC with high glucose or latent heparanase resulted in secretion of vascular endothelial growth factor (VEGF). Primary cardiomyocytes, being a rich source of VEGF, when cocultured with EC, restored EC GPIHBP1 that is lost because of cell passaging. Furthermore, recombinant VEGF induced EC GPIHBP1 mRNA and protein expression within 24 hours, an effect that could be prevented by a VEGF neutralizing antibody. This VEGF-induced increase in GPIHBP1 was through Notch signaling that encompassed Delta-like ligand 4 augmentation and nuclear translocation of the Notch intracellular domain. Finally, cardiomyocytes from severely diabetic animals exhibiting attenuation of VEGF were unable to increase EC GPIHBP1 expression and had lower LPL activity at the vascular lumen in perfused hearts. Conclusion— EC, as the first responders to hyperglycemia, can release heparanase to liberate myocyte VEGF. This growth factor, by activating EC Notch signaling, is responsible for facilitating GPIHBP1-mediated translocation of LPL across EC and regulating LPL-derived fatty acid delivery to the cardiomyocytes.

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“…Apln is a specific marker for vascular endothelial cells (30,31), and Apln-CreER has been utilized to mark vascular endothelial cells (32,33). Fabp4 is expressed in adipocytes of fat tissue and is also highly enriched in vascular endothelial cells (34)(35)(36). To further prove the vascular endothelial specificity of FABP4, we performed immunostaining for FABP4 with VE-CAD or PDGFRA.…”

Section: Col1a2mentioning

confidence: 99%