Subramanian Venkateswaran, Krishnamurthy Prasanna, Singh Krishna, Singh Mahipal
Dept. of Physiology, James H. Quillen College of Medicine, East Tennessee State Univ., PO Box 70576, Johnson City, TN 37614, USA.
Am J Physiol Heart Circ Physiol. 2007 Jan;292(1):H673-83. doi: 10.1152/ajpheart.00569.2006. Epub 2006 Sep 15.
The purpose of this study was to investigate the role of osteopontin (OPN) in diabetic hearts. Diabetes was induced in wild-type (WT) and OPN knockout (KO) mice by using streptozotocin (150 mg/kg) injection. Left ventricular (LV) structural and functional remodeling was studied 30 and 60 days after induction of diabetes. Induction of diabetes increased OPN expression in cardiac myocytes. Heart weight-to-body weight ratio was increased in both diabetic (D) groups. Lung wet weight-to-dry weight ratio was increased only in the WT-D group. Peak left ventricular (LV) developed pressures measured using Langendorff perfusion analyses were reduced to a greater extent in WT-D versus KO-D group. LV end-diastolic pressure-volume curve exhibited a significant leftward shift in WT-D but not in KO-D group. LV end-diastolic diameter, percent fractional shortening, and the ratio of peak velocity of early and late filling (E/A wave) were significantly reduced in WT-D mice as analyzed by echocardiography. The increase in cardiac myocyte apoptosis and fibrosis was significantly higher in the WT-D group. Expression of atrial natriuretic peptide and transforming growth factor-beta1 was significantly increased in the WT-D group. Induction of diabetes increased protein kinase C (PKC) phosphorylation in both groups. However, phosphorylation of PKC-betaII was significantly higher in the WT-D group, whereas phosphorylation of PKC-zeta was significantly higher in the KO-D group. Levels of peroxisome proliferator-activated receptor-gamma were significantly decreased in the WT-D group but not in the KO-D group. Thus increased expression of OPN may play a deleterious role during streptozotocin-induced diabetic cardiomyopathy with effects on cardiac fibrosis, hypertrophy, and myocyte apoptosis.
本研究的目的是探究骨桥蛋白（OPN）在糖尿病心脏中的作用。通过注射链脲佐菌素（150 mg/kg）诱导野生型（WT）和OPN基因敲除（KO）小鼠患糖尿病。在糖尿病诱导后30天和60天研究左心室（LV）结构和功能重塑。糖尿病诱导使心肌细胞中OPN表达增加。两个糖尿病（D）组的心脏重量与体重之比均升高。仅WT-D组的肺湿重与干重之比升高。使用Langendorff灌注分析测得的左心室（LV）最大发展压力在WT-D组比KO-D组降低得更显著。LV舒张末期压力-容积曲线在WT-D组呈现显著左移，而在KO-D组未出现。通过超声心动图分析，WT-D小鼠的LV舒张末期直径、短轴缩短率百分比以及早期和晚期充盈峰值速度之比（E/A波）均显著降低。WT-D组心肌细胞凋亡和纤维化的增加显著更高。WT-D组心房利钠肽和转化生长因子-β1的表达显著增加。糖尿病诱导使两组蛋白激酶C（PKC）磷酸化增加。然而，PKC-βII的磷酸化在WT-D组显著更高，而PKC-ζ的磷酸化在KO-D组显著更高。WT-D组过氧化物酶体增殖物激活受体-γ水平显著降低，而KO-D组未降低。因此，OPN表达增加可能在链脲佐菌素诱导的糖尿病心肌病中发挥有害作用，对心脏纤维化、肥大和心肌细胞凋亡产生影响。
