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

Atherosclerosis. 2011 May;216(1):35-43. doi: 10.1016/j.atherosclerosis.2011.01.018. Epub 2011 Jan 21.

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 (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.

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 AT(2)-receptors may promote fibrosis, proliferation and inflammation in patients with AS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Angiotensin-Converting Enzyme 2
  • 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
  • Calcinosis / metabolism
  • Case-Control Studies
  • Female
  • Fibrosis
  • Finland
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Neovascularization, Pathologic / metabolism
  • Peptidyl-Dipeptidase A / analysis*
  • Proto-Oncogene Proteins / analysis*
  • Proto-Oncogene Proteins / genetics
  • RNA, Messenger / analysis
  • Receptor, Angiotensin, Type 2 / analysis
  • Receptors, Cell Surface / analysis*
  • Receptors, G-Protein-Coupled / analysis*
  • Receptors, G-Protein-Coupled / genetics
  • Renin / analysis
  • Renin / genetics
  • Renin-Angiotensin System* / drug effects
  • Renin-Angiotensin System* / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vacuolar Proton-Translocating ATPases / analysis*
  • Young Adult

Substances

  • ATP6AP2 protein, human
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptor, Angiotensin, Type 2
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • prorenin receptor
  • proto-oncogene proteins c-mas-1
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • Renin
  • Vacuolar Proton-Translocating ATPases