title: Pharmacological activation of AMPK ameliorates perivascular adipose/endothelial dysfunction in a manner interdependent on AMPK and SIRT1.
abstract: Adipose and endothelial dysfunction is tightly associated with cardiovascular diseases in obesity and insulin resistance. Because perivascular adipose tissue (PVAT) surrounds vessels directly and influences vessel functions through paracrine effect, and AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) show similarities in modulation of metabolic pathway, we hypothesized that activation of AMPK and SIRT1 in PVAT might regulate the endothelial function in pathological settings. Thus, in this study, we focused on the regulation of AMPK and SIRT1 activities implicated in adipocytokine expression and endothelial homeostasis under inflammatory conditions by using salicylate, metformin, AICA riboside (AICAR) and resveratrol as AMPK activating agents. We prepared conditioned medium (CM) by stimulating PVAT with palmitic acid (PA) and observed the effects of AMPK activating agents on adipocytokine expression and vessel vasodilation in rats. Moreover, we explored the effects of resveratrol and metformin in fructose-fed rats. We observed that PA stimulation induced inflammation and dysregulation of adipocytokine expression accompanied with reduced AMPK activity and SIRT1 abundance in PVAT. AMPK activating agents inhibited NF-κB p65 phosphorylation and suppressed gene expression of pro-inflammatory adipocytokines, and upregulated adiponectin and PPARγ expression in PVAT in an AMPK/SIRT1-interdependent manner. Meanwhile, CM stimulation impaired endothelium-dependent vasodilation in response to acetylcholine (ACh). Pretreatment of CM with AMPK-activating agents enhanced eNOS phosphorylation in the aorta and restored the loss of endothelium-dependent vasodilation, whereas this action was abolished by co-treatment with AMPK inhibitor compound C or SIRT1 inhibitor nicotinamide. Long-term fructose-feeding in rats induced dysregulation of adipocytokine expression in PVAT and the loss of endothelium-dependent vasodilation, whereas these alterations were reversed by oral administration of resveratrol and metformin. Altogether, pharmacological activation of AMPK beneficially regulated adipocytokine expression in PVAT and thus ameliorated endothelial dysfunction against inflammatory insult in an AMPK/SIRT1-interdependent manner.
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, China.
authors.forename: Na
authors.initials: N
authors.lastname: Xiao
authors.affiliation: Biomedical Sciences, Institute of Chinese Medical Sciences, University of Macau, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Complex Prescription of TMAC-CM, China Pharmaceutical University, China.
authors.forename: Junping
authors.initials: J
authors.lastname: Kou
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, China.
authors.forename: Lianwen
authors.initials: L
authors.lastname: Qi
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Huang
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, China.
authors.forename: Baolin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, China. Electronic address: liukangxyz@gmail.com.
authors.forename: Kang
authors.initials: K
authors.lastname: Liu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D054392:Adipokines / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004032:Diet; D005632:Fructose / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology; D051381:Rats; D000077185:Resveratrol; D012265:Ribonucleotides / Q000494:pharmacology; D056564:Sirtuin 1 / Q000378:metabolism*; D012980:Sodium Salicylate / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D054392:Adipokines; D017077:Culture Media, Conditioned; D016328:NF-kappa B; D012265:Ribonucleotides; D013267:Stilbenes; D019308:Palmitic Acid; D005632:Fructose; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D056564:Sirtuin 1; C031143:AICA ribonucleotide; D000077185:Resveratrol; D012980:Sodium Salicylate
keywords: AICA riboside (PubChem CID: 17513); AMP-activated protein kinase; Acetylcholine (PubChem CID: 75271); Compound C (PubChem CID: 11524144); Endothelial dysfunction; Metformin (PubChem CID: 14219); Nicotinamide (PubChem CID: 936); Palmitic acid (PubChem CID: 985); Perivascular adipose tissue; Phenylephrine (PubChem CID: 5284443); Resveratrol (PubChem CID: 445154); Sirtuin 1; Sodium salicylate (PubChem CID: 16760658)