Dixon I M, Ju H, Jassal D S, Peterson D J
Molecular Cardiology Laboratory, St. Boniface General Hospital Research Centre, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Mol Cell Biochem. 1996 Dec 6;165(1):31-45. doi: 10.1007/BF00229743.
Although increased deposition of collagen proteins has been described after myocardial infarction (MI), little is known of time-dependent transcriptional alteration of specific cardiac collagen sub-types as well as the degradative mechanisms for cardiac collagens in right and left ventricular myocardium remote to large left ventricular infarction. We sought to study collagen mRNA abundance and the deposition of specific collagen subtypes in noninfarcted left and right rat heart muscle at different times after MI. We also assessed the activity of different myocardial matrix metalloproteinases (MMP) using zymography to gain some information about degradative pathways for collagen. Furthermore, we assessed passive compliance properties of the right ventricle in experimental hearts. Finally we investigated the role of the renin angiotensin system in the collagen gene expression by administration of an angiotensin converting enzyme (ACE) inhibitor (ramipril) and an angiotensin II receptor type I antagonist (losartan) in experimental animals. We observed that the mRNA abundance of types I and III collagen were increased 3 days after myocardial infarction in both viable left and uninfarcted right ventricular tissues, that they peaked at 7-14 days, and were maintained at relatively high levels in the 28 and 56 days experimental groups. Stiffness of the right ventricular myocardium was significantly increased in the 56 days experimental group when compared to that of control values. These findings correlated with increased immunohistochemical staining patterns of different collagen species in the surviving right (and left) cardiac interstitium of 14, 28, and 56 day experimental cardiac groups. The elevation of fibrillar collagen mRNA abundance in noninfarcted muscle from ventricular chambers was not significantly altered after treatment of experimental animals with ramipril and losartan for up to 14 days. MMP activity was increased in viable left ventricle at 14, 28 and 56 days and at 14 days in the right ventricle in experimental animals when compared to controls. These results indicated that (1) activation of transcription of collagen types I and III gene occurs in acute and chronic MI, and that fibrillar collagen proteins are deposited in the noninfarcted cardiac interstitium after a lag period relative to increased corresponding mRNA abundance; (2) an increase in MMP activity in chronic experimental hearts indicates that increased collagen deposition may be due to an increment in collagen synthesis rather by reduced degradation of collagen, and that MMP activation may be important in remodeling of the noninfarcted cardiac stroma; (3) an increase of right ventricular stiffness was associated with increased deposition of collagen; (4) as losartan treatment is not associated with any normalization of elevated collagen mRNA abundance, the upregulation of collagen gene expression in this model is not mediated by AT1 receptor; and (5) the reduction of cardiac fibrosis mediated by ACE inhibition and losartan treatment may reside at the post-translational level in cardiac collagen metabolism.
尽管已有研究描述了心肌梗死（MI）后胶原蛋白沉积增加的情况，但对于特定心脏胶原蛋白亚型随时间变化的转录改变，以及左心室大面积梗死灶周边左、右心室心肌中心脏胶原蛋白的降解机制，我们却知之甚少。我们试图研究心肌梗死后不同时间点，未梗死的大鼠左、右心肌中胶原蛋白mRNA丰度及特定胶原蛋白亚型的沉积情况。我们还使用酶谱法评估了不同心肌基质金属蛋白酶（MMP）的活性，以获取有关胶原蛋白降解途径的一些信息。此外，我们评估了实验心脏右心室的被动顺应性。最后，我们通过给实验动物施用血管紧张素转换酶（ACE）抑制剂（雷米普利）和I型血管紧张素II受体拮抗剂（氯沙坦），研究了肾素 - 血管紧张素系统在胶原蛋白基因表达中的作用。我们观察到，在心肌梗死后3天，存活的左心室和未梗死的右心室组织中I型和III型胶原蛋白的mRNA丰度均增加，在7 - 14天达到峰值，并在28天和56天的实验组中维持在相对较高水平。与对照值相比，56天实验组右心室心肌的僵硬度显著增加。这些发现与14天、28天和56天实验心脏组存活的右（和左）心脏间质中不同胶原蛋白种类免疫组化染色模式的增加相关。用雷米普利和氯沙坦治疗实验动物长达14天，心室腔未梗死肌肉中纤维状胶原蛋白mRNA丰度的升高没有显著改变。与对照组相比，实验动物在14天、28天和56天存活的左心室以及14天右心室中MMP活性增加。这些结果表明：（1）I型和III型胶原蛋白基因转录激活发生在急性和慢性心肌梗死中，并且相对于相应mRNA丰度增加，纤维状胶原蛋白在滞后一段时间后沉积在未梗死的心脏间质中；（2）慢性实验心脏中MMP活性增加表明，胶原蛋白沉积增加可能是由于胶原蛋白合成增加而非降解减少，并且MMP激活可能在未梗死心脏基质重塑中起重要作用；（3）右心室僵硬度增加与胶原蛋白沉积增加相关；（4）由于氯沙坦治疗与升高的胶原蛋白mRNA丰度的任何正常化均无关，该模型中胶原蛋白基因表达的上调不是由AT1受体介导的；（5）ACE抑制和氯沙坦治疗介导的心脏纤维化减少可能存在于心脏胶原蛋白代谢的翻译后水平。
