Format

Send to

Choose Destination
Antioxid Redox Signal. 2016 Dec 10;25(17):936-952. Epub 2016 Sep 6.

Metallothionein Prevents Age-Associated Cardiomyopathy via Inhibiting NF-κB Pathway Activation and Associated Nitrative Damage to 2-OGD.

Author information

1
1 School of Pharmaceutical Science, Wenzhou Medical University , Wenzhou, P.R. China .
2
2 The Fifth Affiliated Hospital of Wenzhou Medical University , Lishui, P.R. China .
3
3 Zhejiang Cancer Hospital , Hangzhou, P.R. China .
4
4 The Health Examination Center , the 117th Hospital of Chinese People's Liberation Army, Hangzhou, P.R. China .
5
5 Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University , Wenzhou, P.R. China .
6
6 The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou, P.R. China .
7
7 The First Hospital of Jilin University , Changchun, P.R. China .
8
8 Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville , Louisville, Kentucky.

Abstract

AIMS:

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.

RESULTS:

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.

KEYWORDS:

2-oxoglutarate dehydrogenase; age-associated cardiovascular diseases; inflammation; metallothionein; nitrative damage

PMID:
27477335
PMCID:
PMC5144888
DOI:
10.1089/ars.2016.6648
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center