Impairment of aldehyde dehydrogenase-2 by 4-hydroxy-2-nonenal adduct formation and cardiomyocyte hypertrophy in mice fed a high-fat diet and injected with low-dose streptozotocin.
Impairment of aldehyde dehydrogenase-2 by 4-hydroxy-2-nonenal adduct formation and cardiomyocyte hypertrophy in mice fed a high-fat diet and injected with low-dose streptozotocin.
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DOI：
10.1177/1535370213520109
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发表时间：
2014-05
期刊：
影响因子：
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通讯作者：
Palaniyandi SS
中科院分区：
文献类型：
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作者：
Mali VR;Ning R;Chen J;Yang XP;Xu J;Palaniyandi SS
反应性醛如4-羟基-2-壬烯醛（4 HNE）在心脏病的心肌中产生。4 HNE和其他有毒醛与蛋白质形成加合物，导致细胞损伤和器官功能障碍。醛脱氢酶（ALDH）将有毒醛如4 HNE代谢成无毒代谢物。心脏病患者的ALDH水平和活性均降低。我们研究了ALDH 2活性降低是否有助于高脂饮食和低剂量链脲佐菌素（STZ）注射的小鼠心肌细胞肥大。这些小鼠表现出代谢综合征/2型糖尿病（DM）的大部分特征：血糖水平升高，表现为高血糖症（415.2 ± 18.7 mg/dL vs. 265.2 ± 7.6 mg/dL; P < 0.05），葡萄糖耐受不良伴正常血浆胰岛素水平，提示胰岛素抵抗和肥胖，如从增加的体重（44 ± 3.1对34.50 ± 1.32 g; P < 0.05）和体脂肪明显可见。这些小鼠的心肌ALDH 2活性降低了60%（0.1 ± 0.012对0.04 ± 0.015 mmol/min/mg蛋白; P < 0.05）。心肌4 HNE水平也在高血糖心脏升高。免疫共沉淀实验表明，4 HNE与代谢综合征/2型糖尿病小鼠心肌ALDH 2蛋白形成加合物，与对照组相比，代谢综合征/2型糖尿病小鼠心肌肥厚明显，表现为心脏重量（HW）、HW/胫骨长度比、左心室重量（LV）和心肌细胞肥大。心肌细胞肥大与ALDH 2活性呈负相关（R2 = 0.7; P < 0.05）。最后，在患有代谢综合征/2型DM的小鼠中观察到心功能不全。因此，我们得出结论，ALDH 2活性降低可能会导致心脏肥大和功能障碍的小鼠表现出代谢综合征/2型糖尿病的一些特征时，高脂饮食和低剂量STZ注射。
Reactive aldehydes such as 4-hydroxy-2-nonenal (4HNE) are generated in the myocardium in cardiac disease. 4HNE and other toxic aldehydes form adducts with proteins, leading to cell damage and organ dysfunction. Aldehyde dehydrogenases (ALDHs) metabolize toxic aldehydes such as 4HNE into nontoxic metabolites. Both ALDH levels and activity are reduced in cardiac disease. We examined whether reduced ALDH2 activity contributes to cardiomyocyte hypertrophy in mice fed a high-fat diet and injected with low-dose streptozotocin (STZ). These mice exhibited most of the characteristics of metabolic syndrome/type-2 diabetes mellitus (DM): increased blood glucose levels depicting hyperglycemia (415.2 ± 18.7 mg/dL vs. 265.2 ± 7.6 mg/dL; P < 0.05), glucose intolerance with normal plasma insulin levels, suggesting insulin resistance and obesity as evident from increased weight (44 ± 3.1 vs. 34.50 ± 1.32 g; P < 0.05) and body fat. Myocardial ALDH2 activity was 60% lower in these mice (0.1 ± 0.012 vs. 0.04 ± 0.015 mmol/min/mg protein; P < 0.05). Myocardial 4HNE levels were also elevated in the hyperglycemic hearts. Co-immunoprecipitation study showed that 4HNE formed adducts on myocardial ALDH2 protein in the mice exhibiting metabolic syndrome/type-2 DM, and they had obvious cardiac hypertrophy compared with controls as evident from increased heart weight (HW), HW to tibial length ratio, left ventricular (LV) mass and cardiomyocyte hypertrophy. Cardiomyocyte hypertrophy was correlated inversely with ALDH2 activity (R2 = 0.7; P < 0.05). Finally, cardiac dysfunction was observed in mice with metabolic syndrome/type-2 DM. Therefore, we conclude that reduced ALDH2 activity may contribute to cardiac hypertrophy and dysfunction in mice presenting with some of the characteristics of metabolic syndrome/type-2 DM when on a high-fat diet and low-dose STZ injection.