Rojanathammanee Lalida, Rakoczy Sharlene, Kopchick John, Brown-Borg Holly M
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota, School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, ND, 58203, USA.
Age (Dordr). 2014;36(4):9687. doi: 10.1007/s11357-014-9687-3. Epub 2014 Jul 8.
Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) have been shown to affect processes involved in cellular stress defense, aging, and longevity. This study was designed to identify possible mechanisms of a disrupted GH signaling pathway on stress resistance using growth hormone receptor knockout (GHRKO) mice. GHRKO mice are GH resistant due to the targeted disruption of the GH receptor/binding protein gene, thus preventing GH from binding and exerting its downstream effects. These mice have very low circulating IGF-1 levels and high GH levels, are obese yet insulin sensitive, and live longer than their wild-type controls. Wild-type or GHRKO mice were treated with saline or IGF-1 (WT saline, GHRKO saline, GHRKO IGF-1) two times daily for 7 days. Glutathione S-transferase (GST) activities, proteins, and gene expression were determined. Liver mitochondrial GSTA1, GSTA3, and GSTZ1 proteins were significantly higher in GHRKO when compared to those of WT mice. The 4-hydroxynonenal (4-HNE) GST activity was upregulated in GHRKO mice and was suppressed after IGF-1 administration. Interestingly, thioredoxin (Trx)1, Trx2, thioredoxin reductase (TrxR)1, and TrxR2 messenger RNA (mRNA) levels were significantly higher in the GHRKO as compared to WT mice, and IGF-1 treatment suppressed the expression of each. We also found that glutaredoxin (Grx)2 mRNA and cytosolic Grx activity were higher in GHRKO mice. These results suggest that the detoxification and stress response mechanisms in GHRKO mice are contributed in part by the circulating level of IGF-1.
生长激素（GH）和胰岛素样生长因子1（IGF-1）已被证明会影响细胞应激防御、衰老和长寿相关的过程。本研究旨在利用生长激素受体基因敲除（GHRKO）小鼠，确定GH信号通路破坏对应激抵抗的可能机制。GHRKO小鼠由于GH受体/结合蛋白基因的靶向破坏而对GH产生抗性，从而阻止GH结合并发挥其下游效应。这些小鼠循环中的IGF-1水平极低而GH水平很高，虽肥胖但对胰岛素敏感，并且比其野生型对照寿命更长。野生型或GHRKO小鼠每天用生理盐水或IGF-1处理两次（野生型生理盐水组、GHRKO生理盐水组、GHRKO IGF-1组），持续7天。测定谷胱甘肽S-转移酶（GST）的活性、蛋白和基因表达。与野生型小鼠相比，GHRKO小鼠肝脏线粒体中的GSTA1、GSTA3和GSTZ1蛋白显著更高。GHRKO小鼠中4-羟基壬烯醛（4-HNE）的GST活性上调，而在给予IGF-1后受到抑制。有趣的是，与野生型小鼠相比，GHRKO小鼠中硫氧还蛋白（Trx）1、Trx2、硫氧还蛋白还原酶（TrxR）1和TrxR2信使核糖核酸（mRNA）水平显著更高，而IGF-1处理抑制了每种蛋白的表达。我们还发现GHRKO小鼠中谷氧还蛋白（Grx）2的mRNA和胞质Grx活性更高。这些结果表明，GHRKO小鼠中的解毒和应激反应机制部分是由IGF-1的循环水平促成的。
