title: FGF21 represses cerebrovascular aging via improving mitochondrial biogenesis and inhibiting p53 signaling pathway in an AMPK-dependent manner.
abstract: Cerebrovascular aging has a high relationship with stroke and neurodegenerative disease. In the present study, we evaluated the influence of fibroblast growth factor 21 (FGF21) on angiotensin (Ang II)-mediated cerebrovascular aging in human brain vascular smooth muscle cells (hBVSMCs). Ang II induced remarkable aging-phenotypes in hBVSMCs, including enhanced SA-β-gal staining and NBS1 protein expression. First, we used immunoblotting assay to confirm protein expression of FGF21 receptor (FGFR1) and the co-receptor β-Klotho in cultured hBVSMCs. Second, we found that FGF21 treatment partly prevented the aging-related changes induced by Ang II. FGF21 inhibited Ang II-enhanced ROS production/superoxide anion levels, rescued the Ang II-reduced Complex IV and citrate synthase activities, and suppressed the Ang II-induced meprin protein expression. Third, we showed that FGF21 not only inhibited the Ang II-induced p53 activation, but also blocked the action of Ang II on Siah-1-TRF signaling pathway which is upstream factors for p53 activation. At last, either chemical inhibition of AMPK signaling pathway by a specific antagonist Compound C or knockdown of AMPKα1/2 isoform using siRNA, successfully abolished the anti-aging action of FGF21 in hBVSMCs. These results indicate that FGF21 protects against Ang II-induced cerebrovascular aging via improving mitochondrial biogenesis and inhibiting p53 activation in an AMPK-dependent manner, and highlight the therapeutic value of FGF21 in cerebrovascular aging-related diseases such as stroke and neurodegenerative disease.
authors.affiliation: Department of Geriatrics, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Wang
authors.affiliation: Department of Geriatrics, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Geriatrics, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Ling-Lin
authors.initials: LL
authors.lastname: Liu
authors.affiliation: Department of Geriatrics, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Dang
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Department of Geriatrics, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Li
authors.affiliation: Department of Geriatrics, Southwest Hospital, Third Military Medical University, Chongqing, China. Electronic address: lysi08@126.com.
authors.forename: Liang-Yi
authors.initials: LY
authors.lastname: Si
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology; D001921:Brain / Q000098:blood supply* / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D001678:Organelle Biogenesis; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000098563:Seven in Absentia Proteins
chemical_list: D009687:Nuclear Proteins; C504753:TERF2 protein, human; D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53; C414620:fibroblast growth factor 21; D000804:Angiotensin II; D005346:Fibroblast Growth Factors; D003094:Collagen; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Aging; FGF21; Mitochondrial biogenesis; p53