Metallothionein Prevents Age-Associated Cardiomyopathy via Inhibiting NF-κB Pathway Activation and Associated Nitrative Damage to 2-OGD
Metallothionein Prevents Age-Associated Cardiomyopathy via Inhibiting NF-κB Pathway Activation and Associated Nitrative Damage to 2-OGD
复制标题
金属硫蛋白通过抑制 NF-kappa B 通路激活和相关的 2-OGD 硝基损伤来预防年龄相关性心肌病
DOI：
10.1089/ars.2016.6648
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发表时间：
2016-12-10
影响因子：
6.6
通讯作者：
Jin, Litai
中科院分区：
文献类型：
--
作者：
Cong, Weitao;Niu, Chao;Jin, Litai
目的：心脏特异性金属硫蛋白(MT)的过度表达可延长寿命，但MT对年龄相关性心血管疾病(CVD)的保护作用机制尚不清楚。为了阐明这一点，使用了雄性野生型和两个MT转基因(MT-TG)小鼠系，MM和MT-1(心脏特异性MT过度表达分别约为10倍和80倍)，在三个代表年龄(2-3，9-10和18-20个月)。结果：组织形态学和超声心动图分析显示，MT-TG小鼠与增龄相关的心肌肥大、重构和功能障碍均得到改善。此外，衰老伴随的核因子-kappaB的激活，其特征是核p65移位增加，DNA结合活性增加，炎性细胞因子上调，在很大程度上被MT的过度表达所减弱。用模拟炎症环境的肿瘤坏死因子-α(TNF-α)处理H9c2心肌细胞后，核因子-kappaB活性显著升高，并出现一些与年龄相关的表型。进一步证明，核因子-kappaB的激活通过抑制核因子-kappa B p65基因的表达，在AGE相关和肿瘤坏死因子-α诱导的心脏2-氧戊二酸脱氢酶(2-OGD)亚硝化损伤中起关键作用。MT抑制老年MT-TG心脏和经肿瘤坏死因子-α处理的H9c2MT7心肌细胞的NF-kappaB活化和相关的2-OGD亚硝化损伤；在H9c2MT7心肌细胞中，这些保护作用可通过MT特异性基因沉默而消失。创新与结论：综上所述，这些发现表明MT对年龄相关性心血管疾病的保护作用主要归因于其抑制NF-kappa B和减轻亚硝化损伤对2-OGD的作用。
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-kappa 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-alpha (TNF-alpha), which mimicked an inflammatory environment, significantly increased NF-kappa B activity, and some age-related phenotypes appeared. The NF-kappa B activation was further proved to be pivotal for both age-associated and TNF-alpha-induced nitrative damage to cardiac 2-oxoglutarate dehydrogenase (2-OGD) by virtue of NF-kappa B p65 gene silencing. MT inhibited NF-kappa B activation and associated nitrative damage to cardiac 2-OGD in both old MT-TG hearts and TNF-alpha-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-kappa B inhibition and resultant alleviation of nitrative damage to 2-OGD.