title: Metallothionein Prevents Age-Associated Cardiomyopathy via Inhibiting NF-κB Pathway Activation and Associated Nitrative Damage to 2-OGD.
abstract: Cardiac-specific metallothionein (MT) overexpression extends lifespan, but the mechanism underlying the effect of MT protection against age-associated cardiovascular diseases (CVD) remains elusive. To elucidate this, male wild-type and two lines of MT-transgenic (MT-TG) mice, MM and MT-1 (cardiac-specific overexpressing MT about 10- and 80-fold, respectively) at three representative ages (2-3, 9-10, and 18-20 months), were utilized. A stable human MT2A overexpressing cardiomyocytes (H9c2MT7) was also introduced.
  
  
  
  Histomorphology and echocardiographic analysis revealed that age-associated cardiac hypertrophy, remodeling, and dysfunction were ameliorated in MT-TG mice. Also, aging-accompanied NF-κB activation, characterized by increased nuclear p65 translocation, elevated DNA-binding activity, and upregulation of inflammatory cytokines, was largely attenuated by MT overexpression. Treatment of H9c2 cardiomyocytes with tumor necrosis factor-α (TNF-α), which mimicked an inflammatory environment, significantly increased NF-κB activity, and some age-related phenotypes appeared. The NF-κB activation was further proved to be pivotal for both age-associated and TNF-α-induced nitrative damage to cardiac 2-oxoglutarate dehydrogenase (2-OGD) by virtue of NF-κB p65 gene silencing. MT inhibited NF-κB activation and associated nitrative damage to cardiac 2-OGD in both old MT-TG hearts and TNF-α-treated H9c2MT7 cardiomyocytes; these protective effects were abolished in H9c2MT7 cardiomyocytes by MT-specific gene silencing. Innovation and Conclusion: Together, these findings indicate that the protective effects of MT against age-associated CVD can be attributed mainly to its role in NF-κB inhibition and resultant alleviation of nitrative damage to 2-OGD. Antioxid. Redox Signal. 25, 936-952.
authors.affiliation: 1 School of Pharmaceutical Science, Wenzhou Medical University , Wenzhou, P.R. China .
authors.forename: Weitao
authors.initials: W
authors.lastname: Cong
authors.affiliation: 1 School of Pharmaceutical Science, Wenzhou Medical University , Wenzhou, P.R. China .
authors.forename: Chao
authors.initials: C
authors.lastname: Niu
authors.affiliation: 2 The Fifth Affiliated Hospital of Wenzhou Medical University , Lishui, P.R. China .
authors.forename: Lingchun
authors.initials: L
authors.lastname: Lv
authors.affiliation: 3 Zhejiang Cancer Hospital , Hangzhou, P.R. China .
authors.forename: Maowei
authors.initials: M
authors.lastname: Ni
authors.affiliation: 4 The Health Examination Center , the 117th Hospital of Chinese People's Liberation Army, Hangzhou, P.R. China .
authors.forename: Dandan
authors.initials: D
authors.lastname: Ruan
authors.affiliation: 1 School of Pharmaceutical Science, Wenzhou Medical University , Wenzhou, P.R. China .
authors.forename: Lisha
authors.initials: L
authors.lastname: Chi
authors.affiliation: 5 Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University , Wenzhou, P.R. China .
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1 School of Pharmaceutical Science, Wenzhou Medical University , Wenzhou, P.R. China .
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.affiliation: 6 The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou, P.R. China .
authors.forename: Kungao
authors.initials: K
authors.lastname: Zhan
authors.affiliation: 1 School of Pharmaceutical Science, Wenzhou Medical University , Wenzhou, P.R. China .
authors.forename: Yuanhu
authors.initials: Y
authors.lastname: Xuan
authors.affiliation: 7 The First Hospital of Jilin University , Changchun, P.R. China .
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1 School of Pharmaceutical Science, Wenzhou Medical University , Wenzhou, P.R. China .|8 Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville , Louisville, Kentucky.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.affiliation: 2 The Fifth Affiliated Hospital of Wenzhou Medical University , Lishui, P.R. China .
authors.forename: Tiemin
authors.initials: T
authors.lastname: Wei
authors.affiliation: 7 The First Hospital of Jilin University , Changchun, P.R. China .|8 Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville , Louisville, Kentucky.
authors.forename: Lu
authors.initials: L
authors.lastname: Cai
authors.affiliation: 1 School of Pharmaceutical Science, Wenzhou Medical University , Wenzhou, P.R. China .
authors.forename: Litai
authors.initials: L
authors.lastname: Jin
mesh_terms: D000375:Aging; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D004734:Energy Metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006334:Heart Function Tests; D018836:Inflammation Mediators / Q000378:metabolism; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D008668:Metallothionein; D007655:Ketoglutarate Dehydrogenase Complex
keywords: 2-oxoglutarate dehydrogenase; age-associated cardiovascular diseases; inflammation; metallothionein; nitrative damage