Sun Y, Ratajska A, Weber K T
Department of Internal Medicine, University of Missouri Health Sciences Center, Columbia, USA.
J Mol Cell Cardiol. 1995 Feb;27(2):813-22. doi: 10.1016/0022-2828(95)90088-8.
High density angiotensin converting enzyme (ACE) binding is present in the perivascular fibrosis involving intramyocardial coronary arteries and the microscopic scarring of the myocardium that accompanies chronic elevations in circulating angiotensin II (AngII) and/or aldosterone (ALDO). As a kininase II, ACE degrades bradykinin. Herein we sought to determine whether bradykinin (BK) receptor binding was associated with ACE binding in each of these experimental models. BK receptor binding was localized and quantified by in vitro quantitative autoradiography, using [125I-Tyr8]BK. In serial sections of the same heart hematoxylin and eosin (H&E) and picrosirius red (PSR) staining were utilized to address cardiac myocyte injury and fibrosis, respectively. Four experimental groups were examined: unoperated, untreated, age/sex matched controls: age/sex matched uninephrectomized control rats receiving a high sodium diet; animals that received AngII (9 micrograms/h sc) for 2, 4 or 6 weeks; and uninephrectomized rats on a high sodium diet that received ALDO (0.75 micrograms/h sc) for similar periods of time. We found: (a) myocardial fibrosis, including perivascular fibrosis and microscopic scarring, at week 2 of AngII, but not until week 4 or more of ALDO treatment; (b) low BK receptor binding in normal ventricles that was increased in scars and markedly increased in perivascular fibrosis at week 2 of AngII and each increased further at week 4 and 6 of AngII: (c) low BK receptor binding at week 2 and 4 weeks of ALDO treatment which became markedly increased at fibrous tissue sites at week 6. BK receptor and ACE binding were anatomically coincident and localized to each site of fibrosis in both models. The co-location of BK receptor and ACE binding in these models raises the prospect that fibrous tissue ACE may utilize BK as substrate and BK, in turn, may play a role in fibrous tissue formation.
在涉及心肌内冠状动脉的血管周围纤维化以及伴随循环血管紧张素II（AngII）和/或醛固酮（ALDO）长期升高的心肌微观瘢痕形成中，存在高密度血管紧张素转换酶（ACE）结合。作为激肽酶II，ACE可降解缓激肽。在此，我们试图确定在这些实验模型中，缓激肽（BK）受体结合是否与ACE结合相关。使用[125I-Tyr8]BK，通过体外定量放射自显影对BK受体结合进行定位和定量。在同一心脏的连续切片中，分别使用苏木精和伊红（H&E）染色及苦味酸天狼星红（PSR）染色来评估心肌细胞损伤和纤维化。研究了四个实验组：未手术、未治疗、年龄/性别匹配的对照组；年龄/性别匹配的接受高钠饮食的单侧肾切除对照大鼠；接受AngII（9微克/小时，皮下注射）2、4或6周的动物；以及接受高钠饮食的单侧肾切除大鼠，在相似时间段内接受ALDO（0.75微克/小时，皮下注射）。我们发现：（a）AngII处理2周时出现心肌纤维化，包括血管周围纤维化和微观瘢痕形成，但ALDO处理直到4周或更久才出现；（b）正常心室中BK受体结合较低，在瘢痕中增加，在AngII处理2周时血管周围纤维化中显著增加，在AngII处理4周和6周时进一步增加；（c）ALDO处理2周和4周时BK受体结合较低，在6周时在纤维组织部位显著增加。在两个模型中，BK受体和ACE结合在解剖学上一致且定位于每个纤维化部位。这些模型中BK受体和ACE结合的共定位增加了纤维组织ACE可能利用BK作为底物的可能性，反过来，BK可能在纤维组织形成中发挥作用。
