Shear stress modulates VCAM-1 expression in response to TNF-α and dietary lipids via interferon regulatory factor-1 in cultured endothelium

J. Sherrod Deverse, Angad S. Sandhu, Natalie Mendoza, Christina M. Edwards, Chongxiu Sun, Scott I. Simon, Anthony G. Passerini

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Dyslipidemia is a primary risk factor for cardiovascular disease, but the specific mechanisms that determine the localization of atherosclerotic plaques in arteries are not well defined. Triglyceride-rich lipoproteins (TGRL) isolated from human plasma after a high-fat meal modulate TNF-α-induced VCAM-1 expression in cultured human aortic endothelial cells (HAECs) via an interferon regulatory factor (IRF)-1-dependent transcriptional mechanism. We examined whether fluid shear stress acts as a mediator of IRF-1-dependent VCAM-1 expression in response to cytokine and dietary lipids. IRF-1 and VCAM-1 were examined by immunofluorescence in TNF-α-stimulated HAEC monolayers exposed to TGRL and a linear gradient of shear stress ranging from 0 to 16 dyn/cm2 in a microfluidic device. Shear stress alone modulated TNF-α-induced VCAM-1 expression, eliciting a 150% increase at low shear stress (2 dyn/cm2) and a 70% decrease at high shear stress (12 dyn/cm2) relative to static. These differences correlated with a 60% increase in IRF-1 expression under low shear stress and a 40% decrease under high shear stress. The addition of TGRL along with cytokine activated a fourfold increase in VCAM-1 expression and a twofold increase in IRF-1 expression. The combined effect of shear stress and TGRL on the upregulation of membrane VCAM-1 was abolished by transfection of HAECs with IRF-1-specific small interfering RNA. In a healthy swine model, elevated levels of endothelial IRF-1 were also observed within atherosusceptible regions of the aorta by Western blot analysis and immunohisto-chemistry, implicating arterial hemodynamics in the regulation of IRF-1 expression. These data demonstrate direct roles for fluid shear stress and postprandial TGRL from human serum in the regulation of IRF-1 expression and downstream inflammatory responses in HAECs.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume305
Issue number8
DOIs
StatePublished - Oct 15 2013

Fingerprint

Interferon Regulatory Factor-1
Vascular Cell Adhesion Molecule-1
Endothelium
Lipids
Lipoproteins
Triglycerides
Endothelial Cells
Lab-On-A-Chip Devices
Cytokines
Atherosclerotic Plaques
Dyslipidemias
Small Interfering RNA
Fluorescent Antibody Technique
Transfection
Meals
Aorta
Cardiovascular Diseases
Up-Regulation
Swine
Arteries

Keywords

  • Atherosclerosis
  • Endothelial dysfunction
  • Hemodynamics
  • Hypertriglyceridemia
  • Inflammation
  • Tumor necrosis factor-α
  • Vascular cell adhesion molecule 1

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Shear stress modulates VCAM-1 expression in response to TNF-α and dietary lipids via interferon regulatory factor-1 in cultured endothelium. / Deverse, J. Sherrod; Sandhu, Angad S.; Mendoza, Natalie; Edwards, Christina M.; Sun, Chongxiu; Simon, Scott I.; Passerini, Anthony G.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 305, No. 8, 15.10.2013.

Research output: Contribution to journalArticle

Deverse, J. Sherrod ; Sandhu, Angad S. ; Mendoza, Natalie ; Edwards, Christina M. ; Sun, Chongxiu ; Simon, Scott I. ; Passerini, Anthony G. / Shear stress modulates VCAM-1 expression in response to TNF-α and dietary lipids via interferon regulatory factor-1 in cultured endothelium. In: American Journal of Physiology - Heart and Circulatory Physiology. 2013 ; Vol. 305, No. 8.
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AU - Mendoza, Natalie

AU - Edwards, Christina M.

AU - Sun, Chongxiu

AU - Simon, Scott I.

AU - Passerini, Anthony G.

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AB - Dyslipidemia is a primary risk factor for cardiovascular disease, but the specific mechanisms that determine the localization of atherosclerotic plaques in arteries are not well defined. Triglyceride-rich lipoproteins (TGRL) isolated from human plasma after a high-fat meal modulate TNF-α-induced VCAM-1 expression in cultured human aortic endothelial cells (HAECs) via an interferon regulatory factor (IRF)-1-dependent transcriptional mechanism. We examined whether fluid shear stress acts as a mediator of IRF-1-dependent VCAM-1 expression in response to cytokine and dietary lipids. IRF-1 and VCAM-1 were examined by immunofluorescence in TNF-α-stimulated HAEC monolayers exposed to TGRL and a linear gradient of shear stress ranging from 0 to 16 dyn/cm2 in a microfluidic device. Shear stress alone modulated TNF-α-induced VCAM-1 expression, eliciting a 150% increase at low shear stress (2 dyn/cm2) and a 70% decrease at high shear stress (12 dyn/cm2) relative to static. These differences correlated with a 60% increase in IRF-1 expression under low shear stress and a 40% decrease under high shear stress. The addition of TGRL along with cytokine activated a fourfold increase in VCAM-1 expression and a twofold increase in IRF-1 expression. The combined effect of shear stress and TGRL on the upregulation of membrane VCAM-1 was abolished by transfection of HAECs with IRF-1-specific small interfering RNA. In a healthy swine model, elevated levels of endothelial IRF-1 were also observed within atherosusceptible regions of the aorta by Western blot analysis and immunohisto-chemistry, implicating arterial hemodynamics in the regulation of IRF-1 expression. These data demonstrate direct roles for fluid shear stress and postprandial TGRL from human serum in the regulation of IRF-1 expression and downstream inflammatory responses in HAECs.

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KW - Hypertriglyceridemia

KW - Inflammation

KW - Tumor necrosis factor-α

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