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Metallothionein Prevents Age-Associated Cardiomyopathy via Inhibiting NF-?B 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-?B 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-? (TNF-?), which mimicked an inflammatory environment, significantly increased NF-?B activity, and some age-related phenotypes appeared. The NF-?B activation was further proved to be pivotal for both age-associated and TNF-?-induced nitrative damage to cardiac 2-oxoglutarate dehydrogenase (2-OGD) by virtue of NF-?B p65 gene silencing. MT inhibited NF-?B activation and associated nitrative damage to cardiac 2-OGD in both old MT-TG hearts and TNF-?-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-?B inhibition and resultant alleviation of nitrative damage to 2-OGD. Antioxid. Redox Signal. 25, 936-952.

SUBMITTER: Cong W 

PROVIDER: S-EPMC5144888 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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

Cong Weitao W   Niu Chao C   Lv Lingchun L   Ni Maowei M   Ruan Dandan D   Chi Lisha L   Wang Yang Y   Yu Qing Q   Zhan Kungao K   Xuan Yuanhu Y   Wang Yuehui Y   Tan Yi Y   Wei Tiemin T   Cai Lu L   Jin Litai L  

Antioxidants & redox signaling 20160906 17

<h4>Aims</h4>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  ...[more]

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