title: Pravastatin reduces Marfan aortic dilation.
abstract: BACKGROUND
  The sequelae of aortic root dilation are the lethal consequences of Marfan syndrome. The root dilation is attributable to an imbalance between deposition of matrix elements and metalloproteinases in the aortic medial layer as a result of excessive transforming growth factor-beta signaling. This study examined the efficacy and mechanism of statins in attenuating aortic root dilation in Marfan syndrome and compared effects to the other main proposed preventative agent, losartan.
  
  
  RESULTS
  Marfan mice heterozygous for a mutant allele encoding a cysteine substitution in fibrillin-1 (C1039G) were treated daily from 6 weeks old with pravastatin 0.5 g/L or losartan 0.6 g/L. The end points of aortic root diameter (n=25), aortic thickness, and architecture (n=10), elastin volume (n=5), dp/dtmax (maximal rate of change of pressure) (cardiac catheter; n=20), and ultrastructural analysis with stereology (electron microscopy; n=5) were examined. The aortic root diameters of untreated Marfan mice were significantly increased in comparison to normal mice (0.161 ± 0.001 cm vs 0.252 ± 0.004 cm; P<0.01). Pravastatin (0.22 ± 0.003 cm; P<0.01) and losartan (0.221 ± 0.004 cm; P<0.01) produced a significant reduction in aortic root dilation. Both drugs also preserved elastin volume within the medial layer (pravastatin 0.23 ± 0.02 and losartan 0.29 ± 0.03 vs untreated Marfan 0.19 ± 0.02; P=0.01; normal mice 0.27 ± 0.02). Ultrastructural analysis showed a reduction of rough endoplasmic reticulum in smooth muscle cells with pravastatin (0.022 ± 0.004) and losartan (0.013 ± 0.001) compared to untreated Marfan mice (0.035 ± 0.004; P<0.01).
  
  
  CONCLUSIONS
  Statins are similar to losartan in attenuating aortic root dilation in a mouse model of Marfan syndrome. They appear to act through reducing the excessive protein manufacture by vascular smooth muscle cells, which occurs in the Marfan aorta. As a drug that is relatively well-tolerated for long-term use, it may be useful clinically.
authors.affiliation: Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Darren
authors.initials: D
authors.lastname: McLoughlin
authors.forename: Jonathan
authors.initials: J
authors.lastname: McGuinness
authors.forename: John
authors.initials: J
authors.lastname: Byrne
authors.forename: Eloisa
authors.initials: E
authors.lastname: Terzo
authors.forename: Vilhelmiina
authors.initials: V
authors.lastname: Huuskonen
authors.forename: Hester
authors.initials: H
authors.lastname: McAllister
authors.forename: Alexander
authors.initials: A
authors.lastname: Black
authors.forename: Sinead
authors.initials: S
authors.lastname: Kearney
authors.forename: Elaine
authors.initials: E
authors.lastname: Kay
authors.forename: Arnold D K
authors.initials: AD
authors.lastname: Hill
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
authors.forename: J Mark
authors.initials: JM
authors.lastname: Redmond
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D004108:Dilatation, Pathologic / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000648:ultrastructure; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D008382:Marfan Syndrome / Q000150:complications*; D051379:Mice; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D017035:Pravastatin / Q000627:therapeutic use*; D016896:Treatment Outcome; D017540:Tunica Media / Q000378:metabolism / Q000473:pathology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D004549:Elastin; D019808:Losartan; D017035:Pravastatin