Cardiac collagen remodeling in the cardiomyopathic Syrian hamster and the effect of Losartan
Cardiac collagen remodeling in the cardiomyopathic Syrian hamster and the effect of Losartan
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DOI：
10.1006/jmcc.1997.0420
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发表时间：
1997-07-01
影响因子：
5
通讯作者：
Jasmin, G
中科院分区：
文献类型：
--
作者：
Dixon, IMC;Ju, HS;Jasmin, G
尽管胶原蛋白的沉积增加在心肌病中已被描述，但对于胶原基因转录事件与心肌纤维化的发生、基质金属蛋白酶(MMPs)清除胶原之间的时间关系或血管紧张素转换酶(1)受体对这些事件的调节知之甚少，我们试图研究叙利亚心肌病(CMP)仓鼠在心肌病不同阶段的稳态胶原mRNA丰度和特定胶原亚型的沉积。利用酶谱技术，我们还研究了不同MMPs的明胶溶解活性，以获得一些关于实验性心脏胶原去除的信息。最后，我们观察了AT(1)受体阻断剂(氯沙坦)对胶原重构的影响。MIE观察到，与对照组(F1-β株)相比，四个实验组(35、65、120和200天)左心室组织中I型和III型胶原的mRNA水平均显著升高，而实验右室组织中这些胶原蛋白的mRNA水平仅在35天和200天实验组中显著高于对照组。从相应的mRNA丰度增加开始，经过一段时间的滞后期后，左、右室cMP样本中纤维状胶原沉积增加。65、120和200天实验组给予氯沙坦治疗2周后，与对照组相比，心肌肥厚完全消退与AT(1)受体阻断相关。与F1-β对照组相比，65、120和200天实验组大鼠左室肌纤维胶原含量和胶原mRNA丰度无明显变化，心肌肥厚完全消退。氯沙坦治疗与65天和120天的心肌病样本中的基质金属蛋白酶活性显著降低有关。因此，在这种心肌病模型中，纤维性胶原基因的mRNA丰度在非常早期就出现了升高，随后相应的胶原蛋白在后期的心脏间质中沉积。由于在本文研究的心肌病晚期(120天和200天组)，胶原浓度显著增加，我们的数据支持这样的假设，即在心肌病的进展过程中，胶原的合成超过了胶原的去除能力，然而，在该实验模型中，心肌病阶段升高的基质金属蛋白酶活性可能促进了心肌胶原重构，我们认为在存在氯沙坦的情况下，抑制基质金属蛋白酶的活性可能是该药的一种心肌保护机制。(C)1997年学术出版社有限公司。
Although increased deposition of collagen proteins has been described in cardiomyopathy, little is known of the temporal relationship between events in collagen gene transcription and the occurrence of cardiac fibrosis, the removal of collagen by matrix metalloproteinases (MMPs), or of the regulation of these events by angiotensin AT(1) receptors in this disease, We sought to study steady-state collagen mRNA abundance and the deposition of specific collagen subtypes in right and left ventricular muscle of Syrian cardiomyopathic (CMP) hamsters at different stages of cardiomyopathy. Using zymography, we also investigated the gelatinolytic activities of different MMPs to gain some information about collagen removal in experimental hearts. Finally, we investigated the effect of AT(1) receptor blockade (losartan) on collagen remodeling. Mie observed that the mRNA levels of types I and III collagens were significantly increased in all four experimental groups (35, 65, 120, and 200 day) in left Ventricular tissue when compared to control (F1-beta strain) values, The mRNA levels of these collagen species in experimental right Ventricular tissue samples were only elevated significantly in the 35 and 200 day experimental groups when compared to controls. Fibrillar collagen deposition was elevated in left and right ventricular CMP samples after a lag period from the occurrence of corresponding increases in mRNA abundance. Although 2-week losartan treatment of 65, 120 and 200 day experimental groups had no significant effect on left ventricular fibrillar collagen concentration or collagen mRNA abundance when compared to vehicle-infused CMP hamsters, AT(1) receptor blockade was associated with complete regression of cardiac hypertrophy Both MMP-1 (54 kDa band) and MMP-2 (58 and 62 kDa bands) activities were increased in left ventricular CMP tissues at 65, 120 and 200 days when compared to F1-beta controls. Losartan treatment was associated with significant attenuation of MMP activities in cardiomyopathic samples at 65 and 120 days. Thus, elevation of mRNA abundance of fibrillar collagen genes occurs at very early stages in this model of cardiomyopathy, and corresponding collagen proteins were subsequently deposited in the cardiac interstitium at later stages. As collagen concentration was significantly increased in later stages of cardiomyopathy studied herein (120 and 200 day groups), our data support the hypothesis that collagen synthesis exceeds the capacity of collagen removal during the progression of cardiomyopathy, Nevertheless, cardiac collagen remodeling may be facilitated by elevated MMP activity in cardiomyopathic stages in this experimental model, and we suggested that attenuation of MMP activity in the presence of losartan may be a cardioprotective mechanism of this agent. (C) 1997 Academic Press Limited.