Type

Journal Article

Authors

J Mark Redmond
Harry C Dietz
Arnold D K Hill
Elaine Kay
Sinead Kearney
Alexander Black
Hester McAllister
Vilhelmiina Huuskonen
Eloisa Terzo
John Byrne
and 2 others

Subjects

Pharmacology

Topics
prevention control mice mutant strains dilatation pathologic losartan pathology treatment outcome aorta hydroxymethylglutaryl coa reductase inhibitors male disease models animal complications animals aortic diseases pravastatin angiotensin ii type 1 receptor blockers marfan syndrome mice etiology elastin therapeutic use ultrastructure metabolism tunica media muscle smooth vascular endoplasmic reticulum

Pravastatin reduces Marfan aortic dilation. (2011)

Abstract 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. 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). 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.
Collections Ireland -> Royal College of Surgeons in Ireland -> PubMed

Full list of authors on original publication

J Mark Redmond, Harry C Dietz, Arnold D K Hill, Elaine Kay, Sinead Kearney, Alexander Black, Hester McAllister, Vilhelmiina Huuskonen, Eloisa Terzo, John Byrne and 2 others

Experts in our system

1
Arnold D K Hill
Royal College of Surgeons in Ireland
Total Publications: 110
 
2
Elaine W Kay
Royal College of Surgeons in Ireland
Total Publications: 157