Department of Pharmacology and Toxicology, Biocenter Oulu, Institute of Biomedicine, University of Oulu, Oulu, Finland.
Atherosclerosis. 2011 May;216(1):35-43. doi: 10.1016/j.atherosclerosis.2011.01.018. Epub 2011 Jan 21.
There is increasing evidence that renin-angiotensin system (RAS) may play a major role in the actively regulated fibrocalcific process in aortic valve stenosis (AS), but the gene expression or function of (pro)renin receptor ((P)RR), prorenin and renin or angiotensin converting enzyme 2(ACE2)/angiotensin-(1-7)/Mas receptor axis in calcific aortic valve disease is not known.
We characterized expression of (P)RR, ACE2 and Mas receptor as well as renin, prorenin and angiotensin II type 2 (AT(2)) receptors in human aortic valves, and compared normal control valves (n = 11) with valves obtained from patients with aortic regurgitation (AR, n = 14), AR with fibrosis (n = 20) and AS (n = 61). By immunohistochemistry (P)RR positive staining was seen in the valvular endothelial cells of control and in the neovessels of stenotic valves. By RT-PCR, renin mRNA levels were 72% (P = 0.001) and prorenin mRNA levels 64% lower (P = 0.002) in stenotic aortic valves compared to control valves. ACE2, Mas receptor and AT(2)-receptor mRNA levels were 69% (P < 0.001), 58% (P = 0.008) and 75% (P = 0.001) lower, respectively, in stenotic valves. ACE2 positive staining, existing to lesser extent in stenotic aortic valves, was localized mainly to stromal area in spongiosa layer in control valves.
(P)RR, prorenin and renin are expressed in human aortic valves. We also report for the first time expression of ACE2/angiotensin-(1-7)/-Mas receptor axis in human aortic valve cusps. The downregulation of ACE2/angiotensin-(1-7)/-Mas receptor axis as well as AT(2)-receptors may promote fibrosis, proliferation and inflammation in patients with AS.
越来越多的证据表明，肾素-血管紧张素系统（RAS）可能在主动调节主动脉瓣狭窄（AS）的纤维钙化过程中起主要作用，但（前）肾素受体（（P）RR）、前肾素和肾素或血管紧张素转换酶 2（ACE2）/血管紧张素-（1-7）/Mas 受体轴在钙化性主动脉瓣疾病中的基因表达或功能尚不清楚。
我们描述了（P）RR、ACE2 和 Mas 受体以及肾素、前肾素和血管紧张素 II 型 2（AT（2））受体在人主动脉瓣中的表达，并将正常对照瓣膜（n=11）与主动脉瓣反流（AR，n=14）、AR 伴纤维化（n=20）和 AS（n=61）患者的瓣膜进行了比较。通过免疫组织化学染色，（P）RR 阳性染色可见于对照组和狭窄瓣膜的新生血管的瓣膜内皮细胞中。通过 RT-PCR，与对照组相比，狭窄主动脉瓣中的肾素 mRNA 水平降低了 72%（P=0.001），前肾素 mRNA 水平降低了 64%（P=0.002）。ACE2、Mas 受体和 AT（2）-受体 mRNA 水平分别降低了 69%（P<0.001）、58%（P=0.008）和 75%（P=0.001）。在狭窄的主动脉瓣中，ACE2 的阳性染色存在的程度较低，主要定位于对照组瓣膜海绵层的基质区。
（P）RR、前肾素和肾素在人主动脉瓣中有表达。我们还首次报道了 ACE2/血管紧张素-（1-7）/-Mas 受体轴在人主动脉瓣叶中的表达。ACE2/血管紧张素-（1-7）/-Mas 受体轴以及 AT（2）-受体的下调可能促进 AS 患者的纤维化、增殖和炎症。
