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Antagonistic effect of TNF-alpha and insulin on uncoupling protein 2 (UCP-2) expression and vascular damage
Background:
It has been reported that increased expression of UCP-2 in the vasculature may prevent the development of atherosclerosis in patients with increased production of reactive oxygen species, as in the diabetes, obesity or hypertension. Thus, a greater understanding in the modulation of UCP-2 could improve the atherosclerotic process. However, the effect of TNF-α or insulin modulating UCP-2 in the vascular wall is completely unknown. In this context, we propose to study new molecular mechanisms that help to explain whether the moderate hyperinsulinemia or lowering TNF-α levels might have a protective role against vascular damage mediated by UCP-2 expression levels.
Methods:
We analyzed the effect of insulin or oleic acid in presence or not of TNF-α on UCP-2 expression in murine endothelial and vascular smooth muscle cells. At this step, we wondered if some mechanisms studied in vitro could be of any relevance in vivo. We used the following experimental models: ApoE-/- mice under Western type diet for 2, 6, 12 or 18 weeks, BATIRKO mice under high-fat diet for 16 weeks and 52-week-old BATIRKO mice with o without anti-TNF-α antibody pre-treatment.
Results:
Firstly, we found that TNF-α pre-treatment reduced UCP-2 expression induced by insulin in vascular cells. Secondly, we observed a progressive reduction of UCP-2 levels together with an increase of lipid depots and lesion area in aorta from ApoE-/- mice. In vivo, we also observed that moderate hyperinsulinemic obese BATIRKO mice have lower TNF-α and ROS levels and increased UCP-2 expression levels within the aorta, lower lipid accumulation, vascular dysfunction and macrovascular damage. We also observed that the anti-TNF-α antibody pre-treatment impaired the loss of UCP-2 expression within the aorta and relieved vascular damage observed in 52-week-old BATIRKO mice. Finally, we observed that the pretreatment with iNOS inhibitor prevented UCP-2 reduction induced by TNF-α in vascular cells. Moreover, iNOS levels are augmented in aorta from mice with lower UCP-2 levels and higher TNF-α levels.
Conclusions:
Our data suggest that moderate hyperinsulinemia in response to insulin resistance or lowering of TNF-α levels within the aorta attenuates vascular damage, this protective effect being mediated by UCP-2 expression levels through iNOS.
Insights
Uncoupling protein 2 (UCP-2) protects against vascular damage. Lowering TNF-alpha or moderate hyperinsulinemia increases UCP-2, reducing atherosclerosis. This protective effect is mediated by inducible nitric oxide synthase (iNOS).
Area of Science:
- Vascular Biology
- Metabolic Disease Research
- Immunology
Background:
- Increased uncoupling protein 2 (UCP-2) expression in vasculature may prevent atherosclerosis in conditions like diabetes, obesity, and hypertension.
- Understanding UCP-2 modulation could improve management of the atherosclerotic process.
- The impact of TNF-α and insulin on vascular UCP-2 is largely unknown.
Purpose of the Study:
- To investigate molecular mechanisms by which moderate hyperinsulinemia or reduced TNF-α levels offer protection against vascular damage via UCP-2 expression.
- To elucidate the role of inducible nitric oxide synthase (iNOS) in this protective pathway.
Main Methods:
- Analyzed UCP-2 expression in murine endothelial and vascular smooth muscle cells under insulin, oleic acid, and TNF-α treatment.
- Utilized ApoE-/- mice on a Western diet and BATIRKO mice on a high-fat diet to assess in vivo relevance.
- Administered anti-TNF-α antibody and iNOS inhibitor in experimental models.
Main Results:
- TNF-α reduced insulin-induced UCP-2 expression in vascular cells.
- ApoE-/- mice showed progressive UCP-2 reduction, increased lipid depots, and aortic lesion area.
- Moderate hyperinsulinemic obese BATIRKO mice exhibited lower TNF-α and ROS, increased aortic UCP-2, reduced lipid accumulation, and less vascular damage.
- Anti-TNF-α treatment preserved UCP-2 and attenuated vascular damage in aged BATIRKO mice.
- iNOS inhibition prevented TNF-α-induced UCP-2 reduction; iNOS levels were elevated in aortas with low UCP-2 and high TNF-α.
Conclusions:
- Moderate hyperinsulinemia and reduced TNF-α levels attenuate vascular damage by modulating UCP-2 expression through iNOS.
- These findings highlight a potential therapeutic strategy targeting UCP-2 for atherosclerosis prevention.
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