Fang Han1, Ningning Hou2, Yongping Liu2, Na Huang2, Ruiyan Pan3, Xing Zhang4, Enwen Mao2, Xiaodong Sun5. 1. Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China. 2. Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China. 3. Department of Pharmacology, Weifang Medical University, Weifang, China. 4. Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, China. 5. Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China. Electronic address: xiaodong.sun@wfmc.edu.cn.
Abstract
BACKGROUND: Perivascular adipose tissue (PVAT) attenuates its anti-contractile effect through an endothelial-dependent mechanism that aggravates endothelial dysfunction in obesity. The present study was conducted to explore whether liraglutide could improve vascular dysfunction, including the anti-contractile effect of PVAT and endothelial function, by modulating PVAT-related signaling pathways in obesity. METHODS: C57BL/6 mice were fed a normal-chow diet or a high-fat diet (HFD) with or without liraglutide treatment. Vascular function of the thoracic aorta with or without PVAT were measured. Protein levels of components of the PKA-AMPK-PGC1α and antioxidant signaling pathway in PVAT were determined by western blotting. Brown adipose tissue-related gene in PVAT was measured by qRT-PCR. RESULTS: Metabolic profiles of HFD-fed mice were improved after treatment with liraglutide. Liraglutide improved PVAT-induced anti-contractile capability and PVAT-induced endothelial dysfunction in HFD-fed mice both in vivo and ex vivo. However, blocking PKA, or AMPK, but not cAMP, attenuated these beneficial effects of liraglutide. Treating HFD-fed mice with liraglutide activated the AMPK/eNOS pathway and induced browning-related gene expression. Moreover, liraglutide increased antioxidant capability. The protective effects were related to activation of a cAMP-independent PKA-AMPK pathway, as demonstrated by western blot and PCR. CONCLUSIONS: Liraglutide improved vascular dysfunction by modulating a cAMP-independent PKA-AMPK pathway in PVAT in HFD-induced obese mice. The findings provide a novel mechanism for the cardiovascular protection of liraglutide by modulating PVAT function in obesity.
BACKGROUND: Perivascular adipose tissue (PVAT) attenuates its anti-contractile effect through an endothelial-dependent mechanism that aggravates endothelial dysfunction in obesity. The present study was conducted to explore whether liraglutide could improve vascular dysfunction, including the anti-contractile effect of PVAT and endothelial function, by modulating PVAT-related signaling pathways in obesity. METHODS: C57BL/6 mice were fed a normal-chow diet or a high-fat diet (HFD) with or without liraglutide treatment. Vascular function of the thoracic aorta with or without PVAT were measured. Protein levels of components of the PKA-AMPK-PGC1α and antioxidant signaling pathway in PVAT were determined by western blotting. Brown adipose tissue-related gene in PVAT was measured by qRT-PCR. RESULTS: Metabolic profiles of HFD-fed mice were improved after treatment with liraglutide. Liraglutide improved PVAT-induced anti-contractile capability and PVAT-induced endothelial dysfunction in HFD-fed mice both in vivo and ex vivo. However, blocking PKA, or AMPK, but not cAMP, attenuated these beneficial effects of liraglutide. Treating HFD-fed mice with liraglutide activated the AMPK/eNOS pathway and induced browning-related gene expression. Moreover, liraglutide increased antioxidant capability. The protective effects were related to activation of a cAMP-independent PKA-AMPK pathway, as demonstrated by western blot and PCR. CONCLUSIONS: Liraglutide improved vascular dysfunction by modulating a cAMP-independent PKA-AMPK pathway in PVAT in HFD-induced obesemice. The findings provide a novel mechanism for the cardiovascular protection of liraglutide by modulating PVAT function in obesity.
Authors: Shereen Nizari; Marina Basalay; Philippa Chapman; Nils Korte; Alla Korsak; Isabel N Christie; Shefeeq M Theparambil; Sean M Davidson; Frank Reimann; Stefan Trapp; Derek M Yellon; Alexander V Gourine Journal: Basic Res Cardiol Date: 2021-05-03 Impact factor: 17.165