Omega-3 fatty acids attenuate constitutive and insulin-induced CD36 expression through a suppression of PPARα/γ activity in microvascular endothelial cells

Rosalinda Madonna; Sara Salerni; Deborah Schiavone; Jan F. Glatz; Yong-Jian Geng; Raffaele De Caterin

doi:10.1160/TH10-09-0574

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2011; 106(03): 500-510
DOI: 10.1160/TH10-09-0574

Endothelium and Vascular Development

Schattauer GmbH

Omega-3 fatty acids attenuate constitutive and insulin-induced CD36 expression through a suppression of PPARα/γ activity in microvascular endothelial cells

Rosalinda Madonna

¹Chair of Cardiology, “G. d’Annunzio” University, Chieti, Italy

²Texas Heart Institute, Heart Failure Laboratory, Houston Texas, USA

,

Sara Salerni

¹Chair of Cardiology, “G. d’Annunzio” University, Chieti, Italy

,

Deborah Schiavone

¹Chair of Cardiology, “G. d’Annunzio” University, Chieti, Italy

,

Jan F. Glatz

³Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands

,

Yong-Jian Geng

²Texas Heart Institute, Heart Failure Laboratory, Houston Texas, USA

,

Raffaele De Caterin

¹Chair of Cardiology, “G. d’Annunzio” University, Chieti, Italy

⁴Fondazione G. Monasterio, Pisa, Italy

› Author Affiliations

Abstract

Summary

Microvascular dysfunction occurs in insulin resistance and/or hyperinsulinaemia. Enhanced uptake of free fatty acids (FFA) and oxidised low-density lipoproteins (oxLDL) may lead to oxidative stress and microvascular dysfunction interacting with CD36, a PPARα/γ-regulated scavenger receptor and long-chain FFA transporter. We investigated CD36 expression and CD36-mediated oxLDL uptake before and after insulin treatment in human dermal microvascular endothelial cells (HMVECs), ± different types of fatty acids (FA), including palmitic, oleic, linoleic, arachidonic, eicosapentaenoic (EPA), and docosahexaenoic (DHA) acids. Insulin (10⁻⁸ and 10⁻⁷ M) time-dependently increased DiI-oxLDL uptake and CD36 surface expression (by 30 ± 13%, p<0.05 vs. untreated control after 24 hours incubation), as assessed by ELISA and flow cytometry, an effect that was potentiated by the PI3-kinase inhibitor wortmannin and reverted by the ERK1/2 inhibitor PD98059 and the PPARα/γ antagonist GW9662. A ≥24 hour exposure to 50 μM DHA or EPA, but not other FA, blunted both the constitutive (by 23 ± 3% and 29 ± 2%, respectively, p<0.05 for both) and insulin-induced CD36 expressions (by 45 ± 27 % and 12 ± 3 %, respectively, p<0.05 for both), along with insulin-induced uptake of DiI-oxLDL and the downregulation of phosphorylated endothelial nitric oxide synthase (P-eNOS). At gel shift assays, DHA reverted insulin-induced basal and oxLDL-stimulated transactivation of PPRE and DNA binding of PPARα/γ and NF-κB. In conclusion, omega-3 fatty acids blunt the increased CD36 expression and activity promoted by high concentrations of insulin. Such mechanisms may be the basis for the use of omega-3 fatty acids in diabetic microvasculopathy.

Keywords

Insulin - atherosclerosis - CD36 - omega-3 fatty acids - type 2 diabetes - insulin resistance

Full Text

References

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