Heterozygous deficiency of manganese superoxide dismutase results in severe lipid peroxidation and spontaneous apoptosis in murine myocardium in vivo
Heterozygous deficiency of manganese superoxide dismutase results in severe lipid peroxidation and spontaneous apoptosis in murine myocardium in vivo
复制标题
DOI：
10.1016/j.freeradbiomed.2005.02.009
复制
发表时间：
2005-06-01
影响因子：
7.4
通讯作者：
Scharffetter-Kochanek, K
中科院分区：
文献类型：
--
作者：
Strassburger, M;Bloch, W;Scharffetter-Kochanek, K
为了避免锰超氧化物歧化酶（SOD 2）缺陷小鼠的早期致死性，我们使用了皮肤特异性策略，在SOD 2基因的外显子3侧翼引入loxP位点。令我们惊讶的是，当将雌性角蛋白14 Cre转基因小鼠与SOD 2“floxed”雄性小鼠交配时，由于卵母细胞中角蛋白14启动子驱动的Cre表达，所有后代都是SOD 2杂合子。与关于SOD 2（+/-）小鼠的最初出版物形成鲜明对比，本文报道的混合遗传背景的小鼠（C57 BL/6 x 129/奥拉）在其杂合状态（SOD+/-）下显示出明显的心肌超微结构损伤，伴随线粒体肿胀和破坏以及脂滴积聚，硝基酪氨酸形成增加，和脂质过氧化以及体内心脏中细胞凋亡信号通路的激活。令人惊讶的是，迄今为止未报道的是，我们发现SOD 2 +/-小鼠心脏组织中细胞溶质铜、锌超氧化物歧化酶（SOD 1）的活性显著降低，表明SOD 2（+/-）小鼠心脏中线粒体膜的破坏导致超氧阴离子自由基或其衍生物的释放增强，随后细胞溶质SOD I失活。该模型可能特别适合于对年龄相关性心力衰竭以及其他年龄相关性疾病和组织特异性氧化损伤反应的多基因基础的长期研究。(c)2005年爱思唯尔公司All rights reserved.
To circumvent the early lethality of manganese superoxide dismutase (SOD2)-deficient mice, we have used a skin-specific strategy with introduction of loxP sites flanking exon 3 of the SOD2 gene. To our surprise, when breeding a female keratin 14 Cre transgenic mouse to a SOD2 "floxed" male mouse, due to keratin 14 promoter-driven Cre expression in the oocytes, all offspring were heterozygous for SOD2. In sharp contrast to initial publications on SOD2(+/-) mice, the herein reported mice on a mixed genetic background (C57BL/6 x 129/Ola) in their heterozygous state (SOD+/-) revealed distinct ultrastructural damage of the myocard, with swelling and disruption of mitochondria and accumulation of lipid droplets, increased nitrotyrosine formation, and lipid peroxidation as well as activation of apoptosis signaling pathways in the heart in vivo. Strikingly, and so far unreported, we found a substantial decrease in the activity of the cytosolic copper, zinc superoxide dismutase (SOD1) in the heart tissue of SOD2+/- mice, suggesting that the breakdown of mitochondrial membranes in the heart of SOD2(+/-) mice results in the enhanced release of superoxide anion radicals or derivatives thereof with subsequent inactivation of cytosolic SOD I. This model may be particularly suited to long-term studies on age-related heart failure as well as other age-related diseases and the polygenic base of tissue-specific responses to oxidative injury. (c) 2005 Elsevier Inc. All rights reserved.