A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.
Elife
; 42015 10 27.
Article
em En
| MEDLINE
| ID: mdl-26506064
ABSTRACT
Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCß) as a critical mediator of this pathway and demonstrate that the PKCß inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCß and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Bloqueadores dos Canais de Cálcio
/
Síndrome de Marfan
Tipo de estudo:
Observational_studies
Limite:
Adult
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Animals
/
Child
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Child, preschool
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Humans
Idioma:
En
Revista:
Elife
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Estados Unidos