title: Mineralocorticoid receptor antagonism inhibits vein graft remodeling in mice.
abstract: OBJECTIVE
  Vein graft failure rates resulting from adverse graft remodeling remain high with no effective therapy. The mineralocorticoid receptor (MR) plays a role in pathologic arterial remodeling. We demonstrated recently that the MR is upregulated in venous tissues after grafting and hypothesized that MR inhibition would reduce vein graft remodeling.
  
  
  METHODS
  Reverse transcription polymerase chain reaction and immunoblotting were used to examine the expression of the MR and other components of the renin-angiotensin-aldosterone system in human vein and primary human saphenous vein smooth muscle cells (HSVSMC). Adenoviral reporter gene assays were used to explore MR transcriptional activity in HSVSMC. The effect of MR inhibition on vein graft remodeling in vivo was characterized in a mouse vein graft model.
  
  
  RESULTS
  Messenger RNAs encoding the MR, 11-β-hydroxysteroid dehydrogenase 2, angiotensin type 1 receptor, and the angiotensin-converting enzyme are expressed in whole HSVSMC. MR and 11-β-hydroxysteroid dehydrogenase 2 protein expression is confirmed, and MR-dependent transcriptional regulation is demonstrated at physiologic aldosterone concentrations in HSVSMC. Treatment of mice with the MR antagonist spironolactone, at doses that do not lower blood pressure (20 mg/kg per day), reduces maximal vein graft intima-media thickness by 68%, with an associated reduction in graft inflammatory cell infiltration and fibrosis.
  
  
  CONCLUSIONS
  MR is expressed in human venous tissue and cells and modulates gene expression in HSVSMC in response to physiologic aldosterone concentrations. In vivo, MR inhibition reduces vein graft thickening and inflammation. These preclinical data support the potential to use MR antagonists as novel treatments to preserve vein graft patency.
authors.affiliation: Division of Cardiothoracic Surgery, Tufts Medical Center, Boston, Mass 02111, USA.
authors.forename: Afshin
authors.initials: A
authors.lastname: Ehsan
authors.forename: Adam P
authors.initials: AP
authors.lastname: McGraw
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Aronovitz
authors.forename: Carol
authors.initials: C
authors.lastname: Galayda
authors.forename: Michael S
authors.initials: MS
authors.lastname: Conte
authors.forename: Richard H
authors.initials: RH
authors.lastname: Karas
authors.forename: Iris Z
authors.initials: IZ
authors.lastname: Jaffe
mesh_terms: D000450:Aldosterone / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000601:surgery*; D004195:Disease Models, Animal; D015870:Gene Expression; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013148:Spironolactone / Q000494:pharmacology*; D015854:Up-Regulation; D014654:Vascular Patency / Q000187:drug effects*; D014682:Vena Cava, Inferior / Q000187:drug effects / Q000378:metabolism / Q000601:surgery*
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000450:Aldosterone