孕期尼古丁暴露致成年雄性仔鼠心肌纤维化

Prenatal nicotine exposure induces cardiac fibrosis in adult male offspring

目的研究孕期尼古丁暴露对子代大鼠心射血功能和心肌纤维化的影响。方法尼古丁暴露组孕鼠从妊娠第4~20天每天sc尼古丁6.0 mg·kg-1,连续17 d,正常对照组sc生理盐水。检测孕21 d胎鼠、出生后15和90 d雄性仔鼠的体质量和心脏质量。心电图记录90 d雄性仔鼠的心率;多普勒超声仪检测仔鼠心射血功能,包括每搏输出量(SV)、心输出量(CO)、左室长轴缩短分数(FS)、射血分数(EF)、左室后壁舒张期厚度(LVPWd)和室间隔舒张期厚度(IVSd);电镜检测心肌超微结构,Masson染色定性检测心肌胶原蛋白的沉积,放射免疫法定量检测心肌组织Ⅰ型胶原蛋白水平。结果与正常对照组仔鼠比较,孕期尼古丁暴露组21 d胎鼠和15 d雄性仔鼠心脏质量和体质量下降(P<0.05,P<0.01),但90 d雄性仔鼠的心脏质量和体质量无明显差异。尼古丁暴露组90 d雄性仔鼠心率升高[366±10 vs(418±10)min-1](P<0.05);超声心动图检测显示,CO,FS和EF明显降低(P<0.01),IVSd和LVPWd明显增加(P<0.05,P<0.01);电镜观察显示,心肌纤维紊乱,细胞外基质增加;Masson染色显示,心肌胶原蛋白沉积;放射免疫法检测结果显示,心肌组织Ⅰ型胶原蛋白水平升高[0.59±0.09 vs(0.40±0.05)μg·g-1组织](P<0.01)。结论孕期尼古丁暴露可导致成年雄性仔鼠心肌组织Ⅰ型胶原蛋白水平升高,心肌纤维化,心射血功能下降。这些病理变化可能导致其心血管疾病易感性增加。

OBJECTIVE To investigate the effect of prenatal nicotine exposure on cardiac ejection function and myocardial fibrosis of the offspring of rats. METHODS Pregnant rats were sc given nicotine6.0 mg·kg-1, once daily for 17 d. The body mass and heart mass of the offspring were detected at the 21 th day of gestation, and 15 and 90 d after birth. Heart rate of 90 d offspring was recorded by ECG, and cardiac functions were detected by Doppler ultrasonography, including cardiac output（CO）, stroke volume（SV）,ejection fraction（EF）, left ventricular long axis shortening fraction（FS）, interventricular septum diastolic diameter（IVSd） and left ventricular posterior wal diastolic diameter（LVPWd）. The myocardial ultrastructure was detected under an electron microscope. Masson staining was used to detect the myocardial collagen fiber deposition. The level of collagen protein typeⅠ in heart tissue was detected by radioimmunoassay.RESULTS Compared with control group, prenatal nicotine exposure resulted in a decrease of heart mass and body mass in groups of 21 d fetal rats and 15 d offspring（P〈0.05, P〈0.01）, but had no effect on the90 d offspring. Compared with the normal control group, the heart rate of 90 d offspring increased[366＋10vs（418＋10） min-1]（P〈0.05）, CO, FS and EF decreased（P〈0.01）, and IVSd and LVPWd increased（P〈0.05, P〈0.01）. Electron microscopy revealed that in the heart of nicotine 90 d offspring, myocardial fiber arrangement was loosened and confused, while extracellular matrix increased. Masson staining showed collagen deposited in the myocardium. The level of collagen typeⅠin heart tissue increased[0.59±0.09 vs（0.40±0.05） μg·g-1tissue]（P〈0.01）. CONCLUSION Prenatal nicotine exposure induces the increased level of cardiac collagen typeⅠ, myocardial fibrosis and decrease of cardiac ejection function in adult offspring,which may lead to increased susceptibility to cardiovascular diseases.