Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling
Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling
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DOI：
10.1073/pnas.2136717100
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发表时间：
2003-12-23
影响因子：
11.1
通讯作者：
Otsu, K
中科院分区：
文献类型：
--
作者：
Yamaguchi, O;Higuchi, Y;Otsu, K
心肌梗死（MI）和压力超负荷后发生的左心室重构通常被认为是心力衰竭临床病程的决定因素。然而，这一过程的分子机制仍有待阐明。凋亡信号调节激酶1（apoptosis signal-regulating kinase 1，ASK 1）是一种丝裂原活化蛋白激酶激酶，在应激诱导的细胞凋亡中起重要作用。我们使用ASK 1基因敲除小鼠（ASK（-/-））来检验ASK 1参与左心室重构发展的假设。ASK（-/-）心脏没有形态学或组织学缺陷。超声心动图和心导管检查显示正常的整体结构和功能。结扎冠状动脉或胸主动脉缩窄术（TAC）后4周，测定左室结构和功能重构。与WT小鼠相比，ASK（-/-）在两种实验模型中左心室舒张末期和收缩末期心室尺寸的增加显著较小，缩短分数的减少也较小。与WT小鼠相比，ASK（-/-）小鼠MI或TAC后末端脱氧核苷酸转移酶生物素-dUDP缺口末端标记阳性的心肌细胞数量减少。在分离的大鼠新生心肌细胞中，组成型活性突变体ASK 1的过表达诱导凋亡，而新生ASK（-/-）心肌细胞对H2 O2诱导的凋亡具有抵抗性。体外激酶测定显示WT小鼠MI或TAC后心脏中的ASK 1活性增加。因此，ASK 1通过促进细胞凋亡在调节左心室重构中起重要作用。
Left ventricular remodeling that occurs after myocardial infarction (MI) and pressure overload is generally accepted as a determinant of the clinical course of heart failure. The molecular mechanism of this process, however, remains to be elucidated. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in stress-induced apoptosis. We used ASK1 knockout mice (ASK(-/-)) to test the hypothesis that ASK1 is involved in development of left ventricular remodeling. ASK(-/-) hearts showed no morphological or histological defects. Echocardiography and cardiac catheterization revealed normal global structure and function. Left ventricular structural and functional remodeling were determined 4 weeks after coronary artery ligation or thoracic transverse aortic constriction (TAC). ASK(-/-) had significantly smaller increases in left ventricular end-diastolic and end-systolic ventricular dimensions and smaller decreases in fractional shortening in both experimental models compared with WT mice. The number of terminal deoxynucleotidyl transferase biotin-dUDP nick end-labeling-positive myocytes after MI or TAC was decreased in ASK(-/-) compared with that in WT mice. Overexpression of a constitutively active mutant of ASK1 induced apoptosis in isolated rat neonatal cardiomyocytes, whereas neonatal ASK(-/-) cardiomyocytes were resistant to H2O2-induced apoptosis. An in vitro kinase assay showed increased ASK1 activity in heart after MI or TAC in WT mice. Thus, ASK1 plays an important role in regulating left ventricular remodeling by promoting apoptosis.