Increased mitochondrial ROS generation mediates the loss of the anti-contractile effects of perivascular adipose tissue in high-fat diet obese mice

Author(s)

da Costa, Rafael Menezes ; Fais, Rafael S. ; Dechandt, Carlos R. P. ; Louzada-Junior, Paulo ; Alberici, Luciane C. ; Lobato, Nubia S. ; Tostes, Rita C.

• Document type: Journal article
• Source: British Journal of Pharmacology; v. 174, n. 20, p. 15-pg., 2017-10-01.

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-alpha 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-alpha production in this tissue. Experimental Approach C57Bl/6J and TNF-alpha 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 (O-2(-)) and H2O2 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 O-2(-), dismutation of mitochondria-derived H2O2, uncoupling of oxidative phosphorylation and Rho kinase inhibition, decreased phenylephrine-induced contractions in aortae with PVAT from HFD-fed mice. O-2(.-) and H2O2 were increased in PVAT from HFD-fed mice. Mitochondrial respiration analysis revealed decreased O-2 consumption rates in PVAT from HFD-fed mice. TNF-alpha inhibition reduced H2O2 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-alpha receptors. Generation of H2O2 was prevented in PVAT from TNF-alpha receptor deficient obese mice. Conclusion and Implications TNF-alpha-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. (AU)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 10/17259-9 - Studies on mechanisms of mitochondrial uncoupling by non-esterified fatty acids as a strategy for prevention / treatment of obesity
• Grantee: Luciane Carla Alberici
• Support Opportunities: Research Grants - Young Investigators Grants