(Pro)renin receptors and angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor axis in human aortic valve stenosis

• Published in: Atherosclerosis Vol. 216; no. 1; pp. 35 - 43
• Main Authors: Peltonen, Tuomas, Näpänkangas, Juha, Ohtonen, Pasi, Aro, Jani, Peltonen, Jenni, Soini, Ylermi, Juvonen, Tatu, Satta, Jari, Ruskoaho, Heikki, Taskinen, Panu
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 01-05-2011; Elsevier
• Subjects: (Pro)renin receptor; Adult; Aged; Aged, 80 and over; Angiotensin converting enzyme; angiotensin II; Aortic Valve - chemistry; Aortic Valve - drug effects; Aortic Valve - pathology; Aortic Valve Insufficiency - metabolism; Aortic Valve Stenosis - drug therapy; Aortic Valve Stenosis - genetics; Aortic Valve Stenosis - metabolism; Aortic Valve Stenosis - pathology; atherosclerosis; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Calcification; Calcinosis - metabolism; Cardiology. Vascular system; Cardiovascular; Case-Control Studies; Diseases of the aorta; endothelial cells; Female; Fibrosis; Finland; gene expression; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Immunohistochemistry; inflammation; Male; Mas receptor; Medical sciences; messenger RNA; Middle Aged; Neovascularization, Pathologic - metabolism; patients; peptidyl-dipeptidase A; Peptidyl-Dipeptidase A - analysis; Proto-Oncogene Proteins - analysis; Proto-Oncogene Proteins - genetics; Receptor, Angiotensin, Type 2 - analysis; receptors; Receptors, Cell Surface - analysis; Receptors, G-Protein-Coupled - analysis; Receptors, G-Protein-Coupled - genetics; renin; Renin - analysis; Renin - genetics; renin-angiotensin system; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Vacuolar Proton-Translocating ATPases - analysis; Young Adult; Finland; Calcification; (Pro)renin receptor; Mas receptor; Angiotensin converting enzyme; Fibrosis; Human; Aortic stenosis; Enzyme; Cardiovascular disease; Vascular disease; Peptidases; Renin angiotensin system; Renin; Cardiac valvular disease; Angiotensin; Atherosclerosis; Hydrolases; Aspartic endopeptidases; Aortic valve
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2011.01.018

Abstract Background 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. Methods and results We characterized expression of (P)RR, ACE2 and Mas receptor as well as renin, prorenin and angiotensin II type 2 (AT2 ) 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 AT2 -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. Conclusions (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 AT2 -receptors may promote fibrosis, proliferation and inflammation in patients with AS.