Publication Date:
2011-04-16
Description:
Transforming growth factor-beta (TGFbeta) signaling drives aneurysm progression in multiple disorders, including Marfan syndrome (MFS), and therapies that inhibit this signaling cascade are in clinical trials. TGFbeta can stimulate multiple intracellular signaling pathways, but it is unclear which of these pathways drives aortic disease and, when inhibited, which result in disease amelioration. Here we show that extracellular signal-regulated kinase (ERK) 1 and 2 and Smad2 are activated in a mouse model of MFS, and both are inhibited by therapies directed against TGFbeta. Whereas selective inhibition of ERK1/2 activation ameliorated aortic growth, Smad4 deficiency exacerbated aortic disease and caused premature death in MFS mice. Smad4-deficient MFS mice uniquely showed activation of Jun N-terminal kinase-1 (JNK1), and a JNK antagonist ameliorated aortic growth in MFS mice that lacked or retained full Smad4 expression. Thus, noncanonical (Smad-independent) TGFbeta signaling is a prominent driver of aortic disease in MFS mice, and inhibition of the ERK1/2 or JNK1 pathways is a potential therapeutic strategy for the disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111087/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111087/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Holm, Tammy M -- Habashi, Jennifer P -- Doyle, Jefferson J -- Bedja, Djahida -- Chen, YiChun -- van Erp, Christel -- Lindsay, Mark E -- Kim, David -- Schoenhoff, Florian -- Cohn, Ronald D -- Loeys, Bart L -- Thomas, Craig J -- Patnaik, Samarjit -- Marugan, Juan J -- Judge, Daniel P -- Dietz, Harry C -- P01 AR049698/AR/NIAMS NIH HHS/ -- P01 AR049698-07/AR/NIAMS NIH HHS/ -- R01 AR041135/AR/NIAMS NIH HHS/ -- R01 AR041135-12/AR/NIAMS NIH HHS/ -- R01 AR041135-17/AR/NIAMS NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2011 Apr 15;332(6027):358-61. doi: 10.1126/science.1192149.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21493862" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Anthracenes/pharmacology/therapeutic use
;
Aorta/pathology
;
Aortic Aneurysm/*metabolism/pathology/physiopathology/prevention & control
;
Diphenylamine/analogs & derivatives/pharmacology/therapeutic use
;
Disease Models, Animal
;
Disease Progression
;
Enzyme Activation
;
Losartan/pharmacology/therapeutic use
;
*MAP Kinase Signaling System
;
Marfan Syndrome/drug therapy/*metabolism/pathology
;
Mice
;
Mitogen-Activated Protein Kinase 1/antagonists & inhibitors/*metabolism
;
Mitogen-Activated Protein Kinase 3/antagonists & inhibitors/*metabolism
;
Mitogen-Activated Protein Kinase 8/antagonists & inhibitors/metabolism
;
Protein Kinase Inhibitors/pharmacology/therapeutic use
;
Smad2 Protein/metabolism
;
Smad4 Protein/deficiency/genetics
;
Sulfonamides/pharmacology/therapeutic use
;
Transforming Growth Factor beta/antagonists & inhibitors/immunology/*metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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