Dixon I M, Hao J, Reid N L, Roth J C
Laboratory of Molecular Cardiology, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Faculty of Medicine, University of Manitoba, 351 Tache Avenue, Winnipeg, Canada.
Cardiovasc Res. 2000 May;46(2):286-97. doi: 10.1016/s0008-6363(00)00035-3.
As the pharmacological suppression of angiotensin has been associated with cardioprotective effects in cardiomyopathy, our primary aim was to determine whether the expression of Smad protein components of the cardiac TGF-beta signaling cascade is modulated by chronic AT(1) receptor blockade. Furthermore, we examined the relationship between cardiac Smad protein expression and altered collagen turnover in the cardiomyopathic heart.
Male UM-X7. 1 cardiomyopathic (CMP) Syrian hamsters at early (65 days) and late (200 days) stages of cardiomyopathy were subjected to 4 week losartan (15 mg/kg/day) treatment. Expression of left ventricular (LV) receptor-activated (Smad 2) and common-mediator (Smad 4) Smads from control (F1-beta strain) hamsters, non-treated cardiomyopathic (CMP), and losartan-treated CMP animals was assessed. Collagen turnover, including fibrillar collagen synthesis/accretion and cardiac MMP activity was assessed.
Elevated mRNA abundance of fibrillar collagens and ANF were present in cardiomyopathic hearts and these trends were normalized in the early stage losartan-treated group. 4-Hydroxyproline and zymographic assays confirmed fibrosis and elevated MMP-1 and -2 activities in CMP hearts. Losartan treatment was associated with a modest reduction of cardiac 4-hydroxyproline concentration, and a significant reduction of both MMP-1 and MMP-2 activities. While TGF-beta(1) mRNAs were elevated in both CMP groups vs. controls, total TGF-beta protein content was not different in CMP vs. controls. In LV preparations containing nuclear extract, elevated Smad 2 and Smad 4 protein expression was noted in cardiomyopathic hearts vs. controls. Losartan treatment of late-stage CMP hamsters was associated with a significant reduction in Smad 2 and a modest reduction of Smad 4 protein expression vs. untreated CMP samples.
Altered cardiac Smad expression, present in both early and late stage cardiomyopathy, is positively correlated with the occurrence of cardiac fibrosis and elevated collagen turnover in failing CMP hearts. Four week AT(1) blockade is associated with normalized expression of cardiac Smad 2 proteins, and these changes occur in parallel with some aspects of collagen turnover in failing cardiomyopathic hearts.
由于血管紧张素的药理抑制作用已被证明与心肌病的心脏保护作用相关，我们的主要目的是确定心脏转化生长因子-β信号级联反应的Smad蛋白成分的表达是否受慢性AT(1)受体阻断的调节。此外，我们研究了心脏Smad蛋白表达与心肌病心脏中胶原周转改变之间的关系。
雄性UM-X7.1心肌病（CMP）叙利亚仓鼠在心肌病的早期（65天）和晚期（200天）接受4周氯沙坦（15毫克/千克/天）治疗。评估来自对照（F1-β品系）仓鼠、未治疗的心肌病（CMP）和氯沙坦治疗的CMP动物的左心室（LV）受体激活型（Smad 2）和共同介导型（Smad 4）Smads的表达。评估胶原周转，包括纤维状胶原合成/积聚和心脏基质金属蛋白酶活性。
心肌病心脏中纤维状胶原和心钠素的mRNA丰度升高，而在早期氯沙坦治疗组中这些趋势恢复正常。4-羟脯氨酸和酶谱分析证实CMP心脏中存在纤维化且MMP-1和-2活性升高。氯沙坦治疗与心脏4-羟脯氨酸浓度适度降低以及MMP-1和MMP-2活性显著降低相关。虽然与对照组相比，两个CMP组中的TGF-β(1) mRNA均升高，但CMP组与对照组的总TGF-β蛋白含量并无差异。在含有核提取物的LV制剂中，与对照组相比，心肌病心脏中Smad 2和Smad 4蛋白表达升高。与未治疗的CMP样本相比，氯沙坦治疗晚期CMP仓鼠与Smad 2显著降低和Smad 4蛋白表达适度降低相关。
心肌病早期和晚期均存在的心脏Smad表达改变与衰竭CMP心脏中心脏纤维化的发生和胶原周转增加呈正相关。4周的AT(1)阻断与心脏Smad 2蛋白表达正常化相关，并且这些变化与衰竭心肌病心脏中胶原周转的某些方面同时发生。
