Cardiac-specific overexpression of catalase rescues ventricular myocytes from ethanol-induced cardiac contractile defect.
Cardiac-specific overexpression of catalase rescues ventricular myocytes from ethanol-induced cardiac contractile defect.
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DOI：
10.1016/s0022-2828(03)00080-4
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发表时间：
2003-06
影响因子：
5
通讯作者：
Xiaochun Zhang;Aaron L Klein;Nicholas S Alberle;F. Norby;B. H. Ren;J. Duan;Jun Ren
中科院分区：
文献类型：
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作者：
Xiaochun Zhang;Aaron L Klein;Nicholas S Alberle;F. Norby;B. H. Ren;J. Duan;Jun Ren
氧化应激与酒精性心肌病密切相关。过氧化氢酶负责过氧化氢（H2 O2）的解毒，并可能干扰乙醇诱导的心脏毒性。为了验证这一假设，转基因小鼠品系在心脏中过表达过氧化氢酶（约50倍），范围从肌浆，细胞核和心肌细胞内的过氧化物酶体。在过氧化氢酶转基因（CAT）和野生型FVB小鼠的心室肌细胞中评价机械和细胞内Ca 2+特性。Western blot检测肌浆网Ca ~（2+）-ATP酶（SERCA）、受磷蛋白（PLB）、Na ~+/Ca ~（2+）交换蛋白（NCX）、二氢吡啶Ca ~（2+）受体（DHPR）、兰尼碱受体（RyR）、Akt和磷酸化Akt（pAkt）的蛋白丰度。CAT本身不改变体重和器官重量，以及肌细胞收缩特性。急性乙醇暴露引起FVB小鼠细胞缩短和细胞内Ca 2+浓度依赖性抑制，最大抑制率分别为65.4%和35.8%。乙醇诱导的心肌抑制作用在CAT心肌细胞中明显减弱，最大抑制率分别为42.4%和27.3%。CAT还能解除乙醇对最大缩短/再延长速度、再延长时间和细胞内Ca ~（2+）清除时间的抑制作用。细胞缩短在不同的细胞外Ca 2+显示较强的肌细胞缩短幅度较低（0.5 mM）的Ca 2+在CAT小鼠。CAT小鼠心肌细胞NCX、RyR、Akt和pAkt蛋白表达升高，而SERCA、PLB和DHPR蛋白表达无明显变化。总之，我们的数据表明，过氧化氢酶过表达可以保护心肌细胞从乙醇诱导的收缩缺陷，部分通过改善细胞内Ca 2+处理和Akt信号。
Oxidative stress is intimately involved in alcoholic cardiomyopathy. Catalase is responsible for detoxification of hydrogen peroxide (H2O2) and may interfere with ethanol-induced cardiac toxicity. To test this hypothesis, a transgenic mouse line was produced to overexpress catalase (~50-fold) in the heart, ranging from sarcoplasm, the nucleus and peroxisomes within myocytes. Mechanical and intracellular Ca2+properties were evaluated in ventricular myocytes from catalase transgenic (CAT) and wild-type FVB mice. Protein abundance of sarco (endo) plasmic reticulum Ca2+-ATPase (SERCA), phospholamban (PLB), Na+/Ca2+exchanger (NCX), dihydropyridine Ca2+receptor (DHPR), ryanodine receptor (RyR), Akt and phosphorylated Akt (pAkt) were measured by western blot. CAT itself did not alter body and organ weights, as well as myocyte contractile properties. Acute exposure of ethanol elicited a concentration-dependent depression in cell shortening and intracellular Ca2+in FVB mice with maximal inhibitions of 65.4% and 35.8%, respectively. The ethanol-induced cardiac depression was significantly attenuated in myocytes from CAT with maximal inhibitions of 42.4% and 27.3%. CAT also abrogated the ethanol-induced inhibition of maximal velocity of shortening/relengthening, prolongation of relengthening duration and intracellular Ca2+clearing time. Cell shortening at different extracellular Ca2+revealed stronger myocyte-shortening amplitude under lower (0.5 mM) Ca2+in CAT mice. Protein expression of NCX, RyR, Akt and pAkt were elevated in myocytes from CAT mice, while those of SERCA, PLB and DHPR were not affected. In conclusion, our data suggest that catalase overexpression may protect cardiac myocytes from ethanol-induced contractile defect, partially through improved intracellular Ca2+handling and Akt signaling.