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. 2010 Feb 16:9:9.
doi: 10.1186/1475-2840-9-9.

Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects

Manoj Mathew  1 , Eric Tay, Kenneth Cusi
Affiliations

Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects

Manoj Mathew et al. Cardiovasc Diabetol. .

Abstract

Background: CVD in obesity and T2DM are associated with endothelial activation, elevated plasma vascular inflammation markers and a prothrombotic state. We examined the contribution of FFA to these abnormalities following a 48-hour physiological increase in plasma FFA to levels of obesity and diabetes in a group of healthy subjects.

Methods: 40 non-diabetic subjects (age = 38 +/- 3 yr, BMI = 28 +/- 1 kg/m2, FPG = 95 +/- 1 mg/dl, HbA1c = 5.3 +/- 0.1%) were admitted twice and received a 48-hour infusion of normal saline or low-dose lipid. Plasma was drawn for intracellular (ICAM-1) and vascular (VCAM-1) adhesion molecules-1, E-selectin (sE-S), myeloperoxidase (MPO) and total plasminogen inhibitor-1 (tPAI-1). Insulin sensitivity was measured by a hyperglycemic clamp (M/I).

Results: Lipid infusion increased plasma FFA to levels observed in obesity and T2DM and reduced insulin sensitivity by 27% (p = 0.01). Elevated plasma FFA increased plasma markers of endothelial activation ICAM-1 (138 +/- 10 vs. 186 +/- 25 ng/ml), VCAM-1 (1066 +/- 67 vs. 1204 +/- 65 ng/ml) and sE-S (20 +/- 1 vs. 24 +/- 1 ng/ml) between 13-35% and by > or = 2-fold plasma levels of myeloperoxidase (7.5 +/- 0.9 to 15 +/- 25 ng/ml), an inflammatory marker of future CVD, and tPAI-1 (9.7 +/- 0.6 to 22.5 +/- 1.5 ng/ml), an indicator of a prothrombotic state (all p < or = 0.01). The FFA-induced increase was independent from the degree of adiposity, being of similar magnitude in lean, overweight and obese subjects.

Conclusions: An increase in plasma FFA within the physiological range observed in obesity and T2DM induces markers of endothelial activation, vascular inflammation and thrombosis in healthy subjects. This suggests that even transient (48-hour) and modest increases in plasma FFA may initiate early vascular abnormalities that promote atherosclerosis and CVD.

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Figures

Figure 1
Figure 1
Effect of a 48-hour increase low-dose lipid infusion on insulin sensitivity
Figure 2
Figure 2
Effect of a 48-hour increase low-dose lipid infusion on plasma concentrations of markers of endothelial activation, MPO and tPAI-1
Figure 3
Figure 3
Compared to a saline, FFA increased doubled plasma MPO from 7.5 ± 0.9 to 15 ± 25 ng/ml (p = 0.01) and tPAI-1 by 132% from 9.7 ± 0.6 to 22.5 ± 1.5 ng/ml (p < 0.001)
Figure 4
Figure 4
This figure summarizes the percent increase with lipid infusion of markers of endothelial activation, MPO and tPAI-1
Figure 5
Figure 5
Figure5describes the response in subjects divided by BMI as either lean (BMI <25 kg/m2), overweight (BMI >25 and <30 kg/m2) or obese (BMI >30 kg/m2)
See this image and copyright information in PMC

References

    1. Cernuda-Morollon E, Ridley A. Rho GTPases and leukocyte adhesion receptor expression and function in endothelial cells. Circ Res. 2006;98:757–767. doi: 10.1161/01.RES.0000210579.35304.d3. - DOI - PubMed
    1. Blankenberg S, Barbaux S, L T. Adhesion molecules and atherosclerosis. Atherosclerosis. 2003;170:191–203. doi: 10.1016/S0021-9150(03)00097-2. - DOI - PubMed
    1. Collins T, Read M, Neish A, Whitley M, Thanos D, Maniatis T. Transcriptional regulation of endothelial cell adhesion molecules: NF- kappa B and cytokine-inducible enhancers. FASEB J. 1995;9:899–909. - PubMed
    1. Savoia C, Ernesto L. Vascular inflammation in hypertension and diabetes: molecular mechanisms and therapeutic interventions. Clinical Science. 2007;112:375–384. doi: 10.1042/CS20060247. - DOI - PubMed
    1. Read MA, Read MA, Whitley MZ, Gupta S, Pierce JW, Best J, Davis RJ, Colins T. Tumor necrosis factor alpha-induced E-selectin expression is activated by the nuclear factor-kappaB and c-JUN N-terminal kinase/p38 mitogen-activated protein kinase pathways. The Journal of Biological Chemistry. 1997;272:2753–2761. doi: 10.1074/jbc.272.29.18498. - DOI - PubMed

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