Transcriptional and phenotypic changes in aorta and aortic valve with aging and MnSOD deficiency in mice
Transcriptional and phenotypic changes in aorta and aortic valve with aging and MnSOD deficiency in mice
复制标题
DOI：
10.1152/ajpheart.00735.2012
复制
发表时间：
2013-11-01
影响因子：
4.8
通讯作者：
Miller, Jordan D.
中科院分区：
文献类型：
--
作者：
Roos, Carolyn M.;Hagler, Michael;Miller, Jordan D.
本研究的目的是描述抗氧化剂和年龄相关基因表达的变化，在主动脉和主动脉瓣的老化，并测试的假设，增加线粒体氧化应激加速年龄相关的内皮和主动脉瓣功能障碍。野生型（MnSOD+/+）和锰SOD杂合子单倍不足（MnSOD+/+）小鼠在3和18月龄进行了研究。在野生型小鼠的主动脉中，抗氧化剂的表达得到了保留，尽管Nox 2的表达存在年龄相关的增加。MnSOD单倍不足并不改变主动脉抗氧化剂的表达，但增加了Nox 2的表达。当与主动脉相比，抗氧化剂表达的年龄相关的减少较大的野生型和MnSOD单倍不足的小鼠的主动脉瓣，虽然Nox 2的表达是不变的。同样，sirtuin的表达在两种基因型的主动脉中相对较好地保留，而SIRT 1、SIRT 2、SIRT 3、SIRT 4和SIRT 6的表达在主动脉瓣中显著降低。在MnSOD+/+和MnSOD+/-小鼠的主动脉和主动脉瓣中，细胞衰老的标志物p16（ink 4a）的表达显著增加。在功能上，我们观察到MnSOD+/+和MnSOD+/-小鼠主动脉内皮功能的年龄相关性降低相当。有趣的是，用夹竹桃苷或gp 91 ds-tat抑制NAD（P）H氧化酶改善了MnSOD+/+小鼠的内皮功能，但在两个年龄段的MnSOD+/-小鼠中显著损害了内皮功能。主动脉瓣功能不受衰老或MnSOD单倍功能不全的影响。抗氧化剂和sirtuin基因表达随年龄的变化在主动脉和主动脉瓣之间有显著差异。此外，虽然MnSOD不会导致明显的心血管功能障碍与老化，MnSOD缺乏症的代偿性转录反应似乎是组织特异性的。
The purpose of this study was to characterize changes in antioxidant and age-related gene expression in aorta and aortic valve with aging, and test the hypothesis that increased mitochondrial oxidative stress accelerates age-related endothelial and aortic valve dysfunction. Wild-type (MnSOD+/+) and manganese SOD heterozygous haploinsufficient (MnSOD+/+) mice were studied at 3 and 18 mo of age. In aorta from wild-type mice, antioxidant expression was preserved, although there were age-associated increases in Nox2 expression. Haploinsufficiency of MnSOD did not alter antioxidant expression in aorta, but increased expression of Nox2. When compared with that of aorta, age-associated reductions in antioxidant expression were larger in aortic valves from wild-type and MnSOD haploinsufficient mice, although Nox2 expression was unchanged. Similarly, sirtuin expression was relatively well-preserved in aorta from both genotypes, whereas expression of SIRT1, SIRT2, SIRT3, SIRT4, and SIRT6 were significantly reduced in the aortic valve. Expression of p16(ink4a), a marker of cellular senescence, was profoundly increased in both aorta and aortic valve from MnSOD+/+ and MnSOD+/- mice. Functionally, we observed comparable age-associated reductions in endothelial function in aorta from both MnSOD+/+ and MnSOD+/- mice. Interestingly, inhibition of NAD(P)H oxidase with apocynin or gp91ds-tat improved endothelial function in MnSOD+/+ mice but significantly impaired endothelial function in MnSOD+/- mice at both ages. Aortic valve function was not impaired by aging or MnSOD haploinsufficiency. Changes in antioxidant and sirtuin gene expression with aging differ dramatically between aorta and aortic valve. Furthermore, although MnSOD does not result in overt cardiovascular dysfunction with aging, compensatory transcriptional responses to MnSOD deficiency appear to be tissue specific.