Sun Y, Ramires F J, Weber K T
Department of Internal Medicine, University of Missouri Health Sciences Center, Columbia 65212, USA.
Cardiovasc Res. 1997 Jul;35(1):138-47. doi: 10.1016/s0008-6363(97)00097-7.
Myocardial fibrosis, associated with increased expression of angiotensin converting enzyme (ACE) and bradykinin (BK) receptor binding at sites of tissue repair, accompanies chronic elevations in circulating angiotensin II (AngII) and/or aldosterone (ALDO) that simulate chronic cardiac failure. A role for increased ventricular wall stress, associated with arterial hypertension, that can accompany such neurohormonal activation when ventricular function is not compromised, has been held responsible for this structural remodeling. To address this proposition, we monitored morphology of right and left atria and pulmonary artery, where stress is not increased, and compared these structures with hypertensive aorta.
Experimental groups included: (1) unoperated and untreated controls; (2) intact rats receiving AngII (9 micrograms/h) for 2 weeks and which causes arterial hypertension; (3) uninephrectomized control rats on a high sodium diet for 6 weeks; and (4) uninephrectomized rats receiving ALDO (0.75 micrograms/h) and a high sodium diet for 6 weeks and which results in gradual onset arterial hypertension. Fibrosis was identified by light microscopy in sections stained with collagen specific picrosirius red, while ACE, AngII and BK receptors binding were localized and quantitated by in vitro autoradiography using 125I-351A, 125I[Sar1,Ile8]AngII, and 125I[Tyr8]BK, respectively. AngII receptor subtype was defined by the presence of excess AT1 (losartan) or AT2 (PD123177) receptor antagonists, respectively.
With either AngII or ALDO administration, and compared to controls, we found: (1) microscopic scarring that replaced lost myocytes in both left and right atria; (2) an increase in adventitial collagen of both pulmonary artery and aorta (perivascular fibrosis); (3) markedly increased ACE binding at fibrous tissue sites in both atria and great vessels; (4) unchanged atrial and great vessel AT1 receptor binding; and (5) significantly increased BK receptor binding at sites of atrial and perivascular fibrosis.
Thus, the appearance of atrial fibrosis and perivascular fibrosis of aorta and pulmonary artery, together with associated increase in ACE and BK receptor binding, in rats receiving AngII or ALDO suggests these responses are not related to altered ventricular wall stress or arterial hypertension, but rather to these effector hormones of the circulating renin-angiotensin-aldosterone system. Local BK, regulated by ACE found in fibrous tissue and BK receptor binding may play a role in structural remodeling of atria and great vessels in these rat models that stimulate chronic cardiac failure.
心肌纤维化与组织修复部位血管紧张素转换酶（ACE）表达增加及缓激肽（BK）受体结合增多相关，伴随循环中血管紧张素II（AngII）和/或醛固酮（ALDO）慢性升高，模拟慢性心力衰竭。当心室功能未受损时，与动脉高血压相关的心室壁应力增加可能伴随这种神经激素激活，被认为是这种结构重塑的原因。为验证这一观点，我们监测了右心房、左心房和肺动脉的形态，这些部位应力未增加，并将这些结构与高血压主动脉进行比较。
实验组包括：（1）未手术且未治疗的对照组；（2）完整大鼠接受AngII（9微克/小时）持续2周，可导致动脉高血压；（3）单肾切除的对照大鼠给予高钠饮食6周；（4）单肾切除大鼠接受ALDO（0.75微克/小时）和高钠饮食6周，并导致逐渐发生动脉高血压。通过用胶原特异性苦味酸天狼星红染色的切片进行光学显微镜检查来鉴定纤维化，而ACE、AngII和BK受体结合分别使用125I-351A、125I[Sar1，Ile8]AngII和125I[Tyr8]BK通过体外放射自显影进行定位和定量。AngII受体亚型分别通过存在过量的AT1（氯沙坦）或AT2（PD123177）受体拮抗剂来定义。
给予AngII或ALDO后，与对照组相比，我们发现：（1）显微镜下可见瘢痕形成，替代了左、右心房中丢失的心肌细胞；（2）肺动脉和主动脉外膜胶原增加（血管周围纤维化）；（3）心房和大血管纤维组织部位的ACE结合明显增加；（4）心房和大血管AT1受体结合无变化；（5）心房和血管周围纤维化部位的BK受体结合显著增加。
因此，在接受AngII或ALDO的大鼠中，心房纤维化以及主动脉和肺动脉血管周围纤维化的出现，以及相关的ACE和BK受体结合增加，表明这些反应与心室壁应力改变或动脉高血压无关，而是与循环肾素-血管紧张素-醛固酮系统的这些效应激素有关。在纤维组织中发现的由ACE调节的局部BK和BK受体结合可能在这些模拟慢性心力衰竭的大鼠模型中，在心房和大血管的结构重塑中起作用。
