Effectiveness of combination of losartan potassium and doxycycline versus single-drug treatments in the secondary prevention of thoracic aortic aneurysm in Marfan syndrome.
OBJECTIVE
Losartan potassium (INN losartan), an antihypertensive drug, has been shown to prevent thoracic aortic aneurysm in Marfan syndrome through the inhibition of transforming growth factor beta. Recently we reported that doxycycline, a nonspecific inhibitor of matrix metalloproteinases 2 and 9, normalized aortic vasomotor function and suppressed aneurysm growth. We hypothesized that a combination of losartan potassium and doxycycline would offer better secondary prevention treatment than would single-drug therapy to manage thoracic aortic aneurysm.


METHODS
A well-characterized mouse model of Marfan syndrome (Fbn1(C1039G/+)) was used. At 4 months of age, when aneurysm had established, mice (n = 15/group) were given doxycycline alone (0.24 g/L), losartan potassium alone (0.6 g/L), or combined (0.12-g/L doxycycline and 0.3-g/L losartan potassium) in drinking water. Littermate Fbn1(+/+) mice served as control. Thoracic aortas at 6 and 9 months were studied.


RESULTS
At 9 months, aortic diameter in untreated group was increased by 40% relative to control. Losartan potassium or doxycycline reduced aortic diameter by 10% to 16% versus untreated aortas. Losartan potassium and doxycycline combined completely prevented thoracic aortic aneurysm and improved elastic fiber organization, also downregulating matrix metalloproteinases 2 and 9 and transforming growth factor beta and normalizing aortic contractile and relaxation functions to control values.


CONCLUSIONS
Neither losartan potassium nor doxycycline alone completely restored vascular integrity and cell function when given during delayed treatment, indicating the importance of timed pharmacologic intervention. Combined, however, they synergistically offered better aneurysm-suppressing effects than did single-drug medication in the secondary prevention of thoracic aortic aneurysm.
Yang
H H Clarice
HH
Department of Cardiovascular Science, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Kim
Jong Moo
JM
Chum
Elliott
E
van Breemen
Cornelis
C
Chung
Ada W Y
AW
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017545:Aortic Aneurysm, Thoracic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004318:Doxycycline / Q000008:administration & dosage*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004547:Elastic Tissue / Q000473:pathology; D000071838:Fibrillin-1; D000071837:Fibrillins; D019808:Losartan / Q000008:administration & dosage*; D008382:Marfan Syndrome / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000235:genetics; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000008:administration & dosage*; D055502:Secondary Prevention / Q000379:methods*; D051899:Smad2 Protein / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D054392:Adipokines
D047228:Angiotensin II Type 1 Receptor Blockers; D004318:Doxycycline; D000071838:Fibrillin-1; D000071837:Fibrillins; D019808:Losartan; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008840:Microfilament Proteins; D011480:Protease Inhibitors; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C497783:Smad2 protein, mouse; C522362:Mmp2 protein, mouse; C501830:Mmp9 protein, mouse