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Increased mitochondrial ROS generation mediates the loss of the anti-contractile effects of perivascular adipose tissue in high-fat diet obese mice.
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ABSTRACT: Background and purpose
Obesity is associated with structural and functional changes in perivascular adipose tissue (PVAT), favouring release of reactive oxygen species (ROS), vasoconstrictor and proinflammatory factors. The cytokine TNF-? induces vascular dysfunction and is produced by PVAT. We tested the hypothesis that obesity-associated PVAT dysfunction was mediated by augmented mitochondrial ROS (mROS) generation due to increased TNF-? production in this tissue.Experimental approach
C57Bl/6J and TNF-? receptor-deficient mice received control or high fat diet (HFD) for 18 weeks. We used pharmacological tools to determine the participation of mROS in PVAT dysfunction. Superoxide anion (O2.- ) and H2 O2 were assayed in PVAT and aortic rings were used to assess vascular function.Key results
Aortae from HFD-fed obese mice displayed increased contractions to phenylephrine and loss of PVAT anti-contractile effect. Inactivation of O2.- , dismutation of mitochondria-derived H2 O2 , uncoupling of oxidative phosphorylation and Rho kinase inhibition, decreased phenylephrine-induced contractions in aortae with PVAT from HFD-fed mice. O2.- and H2 O2 were increased in PVAT from HFD-fed mice. Mitochondrial respiration analysis revealed decreased O2 consumption rates in PVAT from HFD-fed mice. TNF-? inhibition reduced H2 O2 levels in PVAT from HFD-fed mice. PVAT dysfunction, i.e. increased contraction to phenylephrine in PVAT-intact aortae, was not observed in HFD-obese mice lacking TNF-? receptors. Generation of H2 O2 was prevented in PVAT from TNF-? receptor deficient obese mice.Conclusion and implications
TNF-?-induced mitochondrial oxidative stress is a key and novel mechanism involved in obesity-associated PVAT dysfunction. These findings elucidate molecular mechanisms whereby oxidative stress in PVAT could affect vascular function.Linked articles
This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc.
SUBMITTER: da Costa RM
PROVIDER: S-EPMC5610168 | biostudies-literature | 2017 Oct
REPOSITORIES: biostudies-literature
Publications
Increased mitochondrial ROS generation mediates the loss of the anti-contractile effects of perivascular adipose tissue in high-fat diet obese mice.
British journal of pharmacology 20170112 20
<h4>Background and purpose</h4>Obesity is associated with structural and functional changes in perivascular adipose tissue (PVAT), favouring release of reactive oxygen species (ROS), vasoconstrictor and proinflammatory factors. The cytokine TNF-α induces vascular dysfunction and is produced by PVAT. We tested the hypothesis that obesity-associated PVAT dysfunction was mediated by augmented mitochondrial ROS (mROS) generation due to increased TNF-α production in this tissue.<h4>Experimental appro ...[more]