凋亡信号调节激酶1在小鼠左心室重塑中的作用

目的 探讨凋亡信号调节激酶1（ASK1）在FVB/N小鼠左心室重塑过程中的变化及其意义。方法 根据FVB/N小鼠心脏重塑过程中不同时间点随机将54只FVB/N小鼠分为0 d组（n=8）、7 d组（n=10）、14 d组（n=16）和21 d组（n=20）。腹腔注射异丙肾上腺素（ISO）建立心脏重塑模型，ISO剂量为每日30 mg/kg，7 d组、14 d组和21 d组分别连续注射7、14、21 d；0 d组腹腔注射等量生理盐水。超声心动图检测小鼠舒张末期左心室后壁厚度（dLVPW）；测量心胫比（HW/TL）；苏木精-伊红染色测量左心室心肌纤维直径；苦味酸-天狼猩红染色检测左心室心肌胶原面积；荧光定量PCR法检测ASK1、Ⅰ型胶原（Collagen Ⅰ）、B型脑钠肽（BNP） mRNA表达水平；观察各组小鼠的死亡率。结果 在注射ISO 0、7、14 d后，小鼠HW/TL、心肌纤维直径、dLVPW逐渐增高（P < 0.05）。与14 d时比较，注射ISO 21 d时，HW/TL及dLVPW差异无统计学意义（P > 0.05），心肌纤维直径减小（P < 0.05）至7 d时水平（P > 0.05）。注射ISO 0、7、14、21 d后，小鼠心脏胶原面积和Collagen Ⅰ mRNA、ASK1 mRNA、BNP mRNA表达量逐渐增高，21 d时达高峰（P < 0.01）。ASK1 mRNA表达量与心脏胶原面积、Collagen Ⅰ mRNA、BNP mRNA表达量均呈正相关，与HW/TL、心肌纤维直径、dLVPW相关性弱。随着ISO注射时间的延长，小鼠的死亡率明显升高。结论 心肌ASK1表达水平与左心室重塑密切相关，ASK1表达水平升高可能导致左心室重塑程度加重，其具体机制有待进一步研究。

Role of apoptosis signal-regulating kinase 1 in left ventricular remodeling in mice

Objective To study the changes and significance of apoptosis signal-regulating kinase 1 (ASK1) in left ventricular remodeling in FVB/N mice. Methods A total of 54 FVB/N mice were randomly divided into 4 groups:0 d group with 8 mice, 7 d group with 10 mice, 14 d group with 16 mice, and 21 d group with 20 mice. A model of cardiac remodeling was established by intraperitoneal injection of isoproterenol (ISO) at a daily dose of 30 mg/kg, and the 7 d, 14 d, and 21 d groups were injected for 7, 14, and 21 consecutive days respectively. The 0 d group was given intraperitoneal injection of an equal volume of normal saline. Echocardiography was used to measure left ventricular posterior wall thickness at end diastole (dLVPW) and the ratio of heart weight to tibia length (HW/TL) was measured. Hematoxylin-eosin staining was used to measure left ventricular myocardial fiber diameter. Picric-Sirius red staining was used to measure myocardial collagen deposition area in the left ventricle. Quantitative real-time PCR was used to measure the mRNA expression of ASK1, type I collagen (collagen I), and B-type natriuretic peptide (BNP). The mortality rate was observed for each group. Results There were gradual increases in HW/TL, myocardial fiber diameter, and dLVPW after 0, 7, and 14 days of ISO injection (P < 0.05). There were no significant changes in HW/TL ratio and dLVPW from days 14 to 21 of ISO injection (P > 0.05), while there was a significant reduction in myocardial fiber diameter (P < 0.05), which was similar to the value on day 7 (P > 0.05). There were significant increases in myocardial collagen deposition area and the mRNA expression of collagen I, ASK1, and BNP after 0, 7, 14, and 21 days of ISO injection, which reached the peaks on day 21 (P < 0.01). The mRNA expression of ASK1 was positively correlated with myocardial collagen deposition area and the mRNA expression of collagen I and BNP and had a weak correlation with HW/TL, myocardial fiber diameter, and dLVPW. There was a significant increase in the mortality rate of the mice over the time of ISO injection. Conclusions The expression of ASK1 in the myocardium is closely associated with left ventricular remodeling. The increase of ASK1 expression may lead to the aggravation of left ventricular remodeling, and the mechanism of which needs further study.