Cardiac oxidative stress in a mouse model of neutral lipid storage disease.
Cardiac oxidative stress in a mouse model of neutral lipid storage disease.
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DOI：
10.1016/j.bbalip.2013.07.004
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发表时间：
2013-11
期刊：
影响因子：
--
通讯作者：
Mayer B
中科院分区：
文献类型：
--
作者：
Schrammel A;Mussbacher M;Winkler S;Haemmerle G;Stessel H;Wölkart G;Zechner R;Mayer B
心脏氧化应激与心肌肥厚、心肌病和心力衰竭的发病机制有关。脂肪甘油三酯脂肪酶（ATGL），催化甘油三酯脂解的限速步骤的酶，编码基因的系统性缺失，导致以严重脂肪变性心功能障碍为特征的表型。本研究的目的是探讨氧化应激在心脏ATGL缺乏症中的潜在作用。将具有整体ATGL敲除的小鼠的心脏与具有心肌细胞限制性ATGL过表达的小鼠的心脏以及野生型同窝小鼠的心脏进行比较。我们的研究结果表明，氧化应激，光泽精化学发光测量，增加了约6倍，在ATGL缺乏的心脏。与此同时，胞浆NADPH氧化酶亚基p67 phox和p47 phox在蛋白质水平上调4-5倍。此外，在这些心脏中观察到不同炎症标志物（肿瘤坏死因子α、单核细胞趋化蛋白-1、白细胞介素6和半乳糖凝集素-3）的显著上调。心肌细胞限制性过表达ATGL后，氧化和炎症反应均被消除。研究氧化和炎症应激对一氧化氮/cGMP信号转导的影响，我们观察到可溶性鸟苷酸环化酶活性上调约2.5倍，心脏四氢生物蝶呤水平增加约2倍。用超氧化物歧化酶模拟物Mn（III）tetrakis（4-苯甲酸）卟啉对ATGL缺陷型小鼠进行全身治疗并没有改善，而是加重了心脏氧化应激。我们的数据表明，氧化和炎症应激似乎参与脂毒性心脏病。可溶性鸟苷酸环化酶和心脏四氢生物蝶呤的上调可能被认为是心脏ATGL缺乏的反调节机制。ATGL（−/−）小鼠患有严重的心脏氧化应激，其来源于NOX 2依赖性NADPH氧化酶的上调。心脏ATGL缺乏时炎症标志物TNFα、MCP-1、IL-6和Mac-2增加。在ATGL（−/−）心脏中，sGC活性和心脏BH 4水平升高。用SOD模拟物MnTBAP对ATGL（−/−）小鼠进行全身治疗并没有改善氧化应激。
Cardiac oxidative stress has been implicated in the pathogenesis of hypertrophy, cardiomyopathy and heart failure. Systemic deletion of the gene encoding adipose triglyceride lipase (ATGL), the enzyme that catalyzes the rate-limiting step of triglyceride lipolysis, results in a phenotype characterized by severe steatotic cardiac dysfunction. The objective of the present study was to investigate a potential role of oxidative stress in cardiac ATGL deficiency. Hearts of mice with global ATGL knockout were compared to those of mice with cardiomyocyte-restricted overexpression of ATGL and to those of wildtype littermates. Our results demonstrate that oxidative stress, measured as lucigenin chemiluminescence, was increased ~ 6-fold in ATGL-deficient hearts. In parallel, cytosolic NADPH oxidase subunits p67phox and p47phox were upregulated 4–5-fold at the protein level. Moreover, a prominent upregulation of different inflammatory markers (tumor necrosis factor α, monocyte chemotactant protein-1, interleukin 6, and galectin-3) was observed in those hearts. Both the oxidative and inflammatory responses were abolished upon cardiomyocyte-restricted overexpression of ATGL. Investigating the effect of oxidative and inflammatory stress on nitric oxide/cGMP signal transduction we observed a ~ 2.5-fold upregulation of soluble guanylate cyclase activity and a ~ 2-fold increase in cardiac tetrahydrobiopterin levels. Systemic treatment of ATGL-deficient mice with the superoxide dismutase mimetic Mn(III)tetrakis (4-benzoic acid) porphyrin did not ameliorate but rather aggravated cardiac oxidative stress. Our data suggest that oxidative and inflammatory stress seems involved in lipotoxic heart disease. Upregulation of soluble guanylate cyclase and cardiac tetrahydrobiopterin might be regarded as counterregulatory mechanisms in cardiac ATGL deficiency. ATGL(−/−) mice suffer from severe cardiac oxidative stress originating from upregulation of NOX2-dependent NADPH oxidase. Inflammation markers TNFα, MCP-1, IL-6, and Mac-2 are increased in cardiac ATGL deficiency. Activity of sGC and cardiac BH4 levels are elevated in ATGL(−/−) hearts. Systemic treatment of ATGL(−/−) mice with the SOD mimetic MnTBAP did not ameliorate oxidative stress.
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DOI：
10.1111/j.1582-4934.2006.tb00304.x
发表时间：
2006-01
影响因子：
5.3
作者：
Moe KT;Aulia S;Jiang F;Chua YL;Koh TH;Wong MC;Dusting GJ
通讯作者：
Dusting GJ
影响因子：
8.3
作者：
Li, JM;Gall, NP;Shah, AM
通讯作者：
Shah, AM
影响因子：
5
作者：
Moens AL;Ketner EA;Takimoto E;Schmidt TS;O'Neill CA;Wolin MS;Alp NJ;Channon KM;Kass DA
通讯作者：
Kass DA
DOI：
10.1073/pnas.1002178107
发表时间：
2010-08-31
影响因子：
11.1
作者：
Kuroda, Junya;Ago, Tetsuro;Sadoshima, Junichi
通讯作者：
Sadoshima, Junichi
影响因子：
15.9
作者：
Landmesser, U;Dikalov, S;Harrison, DG
通讯作者：
Harrison, DG