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Preserved endothelial function in human obesity in the absence of insulin resistance.

El Assar M, Ruiz de Adana JC, Angulo J, Pindado Martínez ML, Hernández Matías A, Rodríguez-Mañas L - J Transl Med (2013)

Bottom Line: NADPH oxidase inhibitors (apocynin and VAS2870) and the nitric oxide synthase (NOS) cofactor, tetrahydrobiopterin failed to modify BK-induced vasodilatations.Superoxide generation was higher in vessels from IR-MO subjects and reduced by mito-TEMPO.Blockade of TNF-α with infliximab, but not inhibition of inducible NOS or cyclooxygenase, improved endothelial relaxation and decreased superoxide formation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Fundación para la Investigación Biomédica, Hospital Universitario de Getafe, Madrid, Spain. leocadio.rodriguez@salud.madrid.org.

ABSTRACT

Background: Insulin resistance (IR) is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular disease (CVD). On the other hand, obesity has long been related to IR and increased CVD. However it is not known if IR is a necessary condition for endothelial dysfunction in human obesity, allowing for preserved endothelial function in obese people when absent. Therefore, the purpose of the study was to assess the relationship between IR and endothelial dysfunction in human obesity and the mechanisms involved.

Methods: Twenty non-insulin resistant morbid obese (NIR-MO), 32 insulin resistant morbid obese (IR-MO), and 12 healthy subjects were included. Serum concentrations of glucose, insulin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), resistin and adiponectin were determined. IR was evaluated by HOMA-index. Endothelium-dependent relaxation to bradykinin (BK) in mesenteric microvessels was assessed in wire myograph.

Results: Serum IL-6, and TNF-α levels were elevated only in IR-MO patients while resistin was elevated and adiponectin reduced in all MO individuals. Mesenteric arteries from IR-MO, but not from NIR-MO subjects displayed blunted relaxation to BK. Vasodilatation was improved in IR-MO arteries by the superoxide scavenger, superoxide dismutase (SOD) or the mitochondrial-targeted SOD mimetic, mito-TEMPO. NADPH oxidase inhibitors (apocynin and VAS2870) and the nitric oxide synthase (NOS) cofactor, tetrahydrobiopterin failed to modify BK-induced vasodilatations. Superoxide generation was higher in vessels from IR-MO subjects and reduced by mito-TEMPO. Blockade of TNF-α with infliximab, but not inhibition of inducible NOS or cyclooxygenase, improved endothelial relaxation and decreased superoxide formation.

Conclusions: Endothelial dysfunction is observed in human morbid obesity only when insulin resistance is present. Mechanisms involved include augmented mitochondrial superoxide generation, and increased systemic inflammation mediated by TNF-α. These findings may explain the different vascular risk of healthy vs unhealthy obesity.

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Role of inflammation on endothelial dysfunction in morbid obese subjects with insulin resistance (IR-MO). Effects of preincubation with the iNOS inhibitor, 1400W (10 μmol/l) (A), the COX inhibitor, indomethacin (10 μmol/l) (B), and the anti-TNF-α, infliximab (100 μmol/l) (C) on the relaxant response to bradykinin (BK) in isolated mesenteric microvessels from IR-MO. Data are expressed as mean±SEM of the percentage of the contraction elicited by K+. N= the number of subjects/n= the number of vascular segments. *p< 0.05 vs IR-MO subjects by two-factors ANOVA.
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Figure 4: Role of inflammation on endothelial dysfunction in morbid obese subjects with insulin resistance (IR-MO). Effects of preincubation with the iNOS inhibitor, 1400W (10 μmol/l) (A), the COX inhibitor, indomethacin (10 μmol/l) (B), and the anti-TNF-α, infliximab (100 μmol/l) (C) on the relaxant response to bradykinin (BK) in isolated mesenteric microvessels from IR-MO. Data are expressed as mean±SEM of the percentage of the contraction elicited by K+. N= the number of subjects/n= the number of vascular segments. *p< 0.05 vs IR-MO subjects by two-factors ANOVA.

Mentions: In mesenteric arteries derived from IR-MO subjects, neither iNOS selective inhibitor 1400W (10 μmol/l) (Figure 4A), nor the cyclooxygenase inhibitor indomethacin (10 μmol/l) (Figure 4B) modified the impaired endothelial function observed in these subjects. By contrast, the anti-TNF-α, infliximab (100 μmol/l), improved the relaxation to BK in arteries from IR-MO subjects (Figure 4C). Interestingly, TNF-α blockade with infliximab also resulted in decreased generation of superoxide in these arteries (Figure 3A-B). None of those three compounds had any effect on endothelium-dependent vasodilation in microvessels derived from NIR-MO (pD2 for BK: 7.67±0.26 vs. 7.57±0.48, 7.23±0.29 vs. 7.00±0.55 and 7.47±0.26 vs. 7.59±0.01, for 1400W, indomethacin and infliximab, respectively).


Preserved endothelial function in human obesity in the absence of insulin resistance.

El Assar M, Ruiz de Adana JC, Angulo J, Pindado Martínez ML, Hernández Matías A, Rodríguez-Mañas L - J Transl Med (2013)

Role of inflammation on endothelial dysfunction in morbid obese subjects with insulin resistance (IR-MO). Effects of preincubation with the iNOS inhibitor, 1400W (10 μmol/l) (A), the COX inhibitor, indomethacin (10 μmol/l) (B), and the anti-TNF-α, infliximab (100 μmol/l) (C) on the relaxant response to bradykinin (BK) in isolated mesenteric microvessels from IR-MO. Data are expressed as mean±SEM of the percentage of the contraction elicited by K+. N= the number of subjects/n= the number of vascular segments. *p< 0.05 vs IR-MO subjects by two-factors ANOVA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016214&req=5

Figure 4: Role of inflammation on endothelial dysfunction in morbid obese subjects with insulin resistance (IR-MO). Effects of preincubation with the iNOS inhibitor, 1400W (10 μmol/l) (A), the COX inhibitor, indomethacin (10 μmol/l) (B), and the anti-TNF-α, infliximab (100 μmol/l) (C) on the relaxant response to bradykinin (BK) in isolated mesenteric microvessels from IR-MO. Data are expressed as mean±SEM of the percentage of the contraction elicited by K+. N= the number of subjects/n= the number of vascular segments. *p< 0.05 vs IR-MO subjects by two-factors ANOVA.
Mentions: In mesenteric arteries derived from IR-MO subjects, neither iNOS selective inhibitor 1400W (10 μmol/l) (Figure 4A), nor the cyclooxygenase inhibitor indomethacin (10 μmol/l) (Figure 4B) modified the impaired endothelial function observed in these subjects. By contrast, the anti-TNF-α, infliximab (100 μmol/l), improved the relaxation to BK in arteries from IR-MO subjects (Figure 4C). Interestingly, TNF-α blockade with infliximab also resulted in decreased generation of superoxide in these arteries (Figure 3A-B). None of those three compounds had any effect on endothelium-dependent vasodilation in microvessels derived from NIR-MO (pD2 for BK: 7.67±0.26 vs. 7.57±0.48, 7.23±0.29 vs. 7.00±0.55 and 7.47±0.26 vs. 7.59±0.01, for 1400W, indomethacin and infliximab, respectively).

Bottom Line: NADPH oxidase inhibitors (apocynin and VAS2870) and the nitric oxide synthase (NOS) cofactor, tetrahydrobiopterin failed to modify BK-induced vasodilatations.Superoxide generation was higher in vessels from IR-MO subjects and reduced by mito-TEMPO.Blockade of TNF-α with infliximab, but not inhibition of inducible NOS or cyclooxygenase, improved endothelial relaxation and decreased superoxide formation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Fundación para la Investigación Biomédica, Hospital Universitario de Getafe, Madrid, Spain. leocadio.rodriguez@salud.madrid.org.

ABSTRACT

Background: Insulin resistance (IR) is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular disease (CVD). On the other hand, obesity has long been related to IR and increased CVD. However it is not known if IR is a necessary condition for endothelial dysfunction in human obesity, allowing for preserved endothelial function in obese people when absent. Therefore, the purpose of the study was to assess the relationship between IR and endothelial dysfunction in human obesity and the mechanisms involved.

Methods: Twenty non-insulin resistant morbid obese (NIR-MO), 32 insulin resistant morbid obese (IR-MO), and 12 healthy subjects were included. Serum concentrations of glucose, insulin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), resistin and adiponectin were determined. IR was evaluated by HOMA-index. Endothelium-dependent relaxation to bradykinin (BK) in mesenteric microvessels was assessed in wire myograph.

Results: Serum IL-6, and TNF-α levels were elevated only in IR-MO patients while resistin was elevated and adiponectin reduced in all MO individuals. Mesenteric arteries from IR-MO, but not from NIR-MO subjects displayed blunted relaxation to BK. Vasodilatation was improved in IR-MO arteries by the superoxide scavenger, superoxide dismutase (SOD) or the mitochondrial-targeted SOD mimetic, mito-TEMPO. NADPH oxidase inhibitors (apocynin and VAS2870) and the nitric oxide synthase (NOS) cofactor, tetrahydrobiopterin failed to modify BK-induced vasodilatations. Superoxide generation was higher in vessels from IR-MO subjects and reduced by mito-TEMPO. Blockade of TNF-α with infliximab, but not inhibition of inducible NOS or cyclooxygenase, improved endothelial relaxation and decreased superoxide formation.

Conclusions: Endothelial dysfunction is observed in human morbid obesity only when insulin resistance is present. Mechanisms involved include augmented mitochondrial superoxide generation, and increased systemic inflammation mediated by TNF-α. These findings may explain the different vascular risk of healthy vs unhealthy obesity.

Show MeSH
Related in: MedlinePlus