ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene
Cardiomyopathy caused by lamin A/C gene mutations (LMNA cardiomyopathy) is characterized by increased myocardial fibrosis, which impairs left ventricular relaxation and predisposes to heart failure, and cardiac conduction abnormalities. While we previously discovered abnormally elevated extracellula...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Oxford University Press
2017
|
| _version_ | 1826264668185821184 |
|---|---|
| author | Chatzifrangkeskou, M Le Dour, C Wu, W Morrow, J Joseph, L Beuvin, M Sera, F Homma, S Vignier, N Mougenot, N Bonne, G Lipson, K Worman, H Muchir, A |
| author_facet | Chatzifrangkeskou, M Le Dour, C Wu, W Morrow, J Joseph, L Beuvin, M Sera, F Homma, S Vignier, N Mougenot, N Bonne, G Lipson, K Worman, H Muchir, A |
| author_sort | Chatzifrangkeskou, M |
| collection | OXFORD |
| description | Cardiomyopathy caused by lamin A/C gene mutations (LMNA cardiomyopathy) is characterized by increased myocardial fibrosis, which impairs left ventricular relaxation and predisposes to heart failure, and cardiac conduction abnormalities. While we previously discovered abnormally elevated extracellular signal-regulated kinase 1/2 (ERK1/2) activities in heart in LMNA cardiomyopathy, its role on the development of myocardial fibrosis remains unclear. We now showed that transforming growth factor (TGF)-β/Smad signaling participates in the activation of ERK1/2 signaling in LMNA cardiomyopathy. ERK1/2 acts on connective tissue growth factor (CTGF/CCN2) expression to mediate the myocardial fibrosis and left ventricular dysfunction. Studies in vivo demonstrate that inhibiting CTGF/CCN2 using a specific antibody decreases myocardial fibrosis and improves the left ventricular dysfunction. Together, these findings show that cardiac ERK1/2 activity is modulated in part by TGF-β/Smad signaling, leading to altered activation of CTGF/CCN2 to mediate fibrosis and alter cardiac function. This identifies a novel mechanism in the development of LMNA cardiomyopathy. |
| first_indexed | 2024-03-06T20:11:32Z |
| format | Journal article |
| id | oxford-uuid:2aba226b-5706-430b-8e19-d987618614b9 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:11:32Z |
| publishDate | 2017 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:2aba226b-5706-430b-8e19-d987618614b92022-03-26T12:26:46ZERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C geneJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2aba226b-5706-430b-8e19-d987618614b9EnglishSymplectic Elements at OxfordOxford University Press2017Chatzifrangkeskou, MLe Dour, CWu, WMorrow, JJoseph, LBeuvin, MSera, FHomma, SVignier, NMougenot, NBonne, GLipson, KWorman, HMuchir, ACardiomyopathy caused by lamin A/C gene mutations (LMNA cardiomyopathy) is characterized by increased myocardial fibrosis, which impairs left ventricular relaxation and predisposes to heart failure, and cardiac conduction abnormalities. While we previously discovered abnormally elevated extracellular signal-regulated kinase 1/2 (ERK1/2) activities in heart in LMNA cardiomyopathy, its role on the development of myocardial fibrosis remains unclear. We now showed that transforming growth factor (TGF)-β/Smad signaling participates in the activation of ERK1/2 signaling in LMNA cardiomyopathy. ERK1/2 acts on connective tissue growth factor (CTGF/CCN2) expression to mediate the myocardial fibrosis and left ventricular dysfunction. Studies in vivo demonstrate that inhibiting CTGF/CCN2 using a specific antibody decreases myocardial fibrosis and improves the left ventricular dysfunction. Together, these findings show that cardiac ERK1/2 activity is modulated in part by TGF-β/Smad signaling, leading to altered activation of CTGF/CCN2 to mediate fibrosis and alter cardiac function. This identifies a novel mechanism in the development of LMNA cardiomyopathy. |
| spellingShingle | Chatzifrangkeskou, M Le Dour, C Wu, W Morrow, J Joseph, L Beuvin, M Sera, F Homma, S Vignier, N Mougenot, N Bonne, G Lipson, K Worman, H Muchir, A ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene |
| title | ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene |
| title_full | ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene |
| title_fullStr | ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene |
| title_full_unstemmed | ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene |
| title_short | ERK1/2 directly acts on CTGF/CCN2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin A/C gene |
| title_sort | erk1 2 directly acts on ctgf ccn2 expression to mediate myocardial fibrosis in cardiomyopathy caused by mutations in the lamin a c gene |
| work_keys_str_mv | AT chatzifrangkeskoum erk12directlyactsonctgfccn2expressiontomediatemyocardialfibrosisincardiomyopathycausedbymutationsinthelaminacgene AT ledourc erk12directlyactsonctgfccn2expressiontomediatemyocardialfibrosisincardiomyopathycausedbymutationsinthelaminacgene AT wuw erk12directlyactsonctgfccn2expressiontomediatemyocardialfibrosisincardiomyopathycausedbymutationsinthelaminacgene AT morrowj erk12directlyactsonctgfccn2expressiontomediatemyocardialfibrosisincardiomyopathycausedbymutationsinthelaminacgene AT josephl erk12directlyactsonctgfccn2expressiontomediatemyocardialfibrosisincardiomyopathycausedbymutationsinthelaminacgene AT beuvinm erk12directlyactsonctgfccn2expressiontomediatemyocardialfibrosisincardiomyopathycausedbymutationsinthelaminacgene AT seraf erk12directlyactsonctgfccn2expressiontomediatemyocardialfibrosisincardiomyopathycausedbymutationsinthelaminacgene AT hommas erk12directlyactsonctgfccn2expressiontomediatemyocardialfibrosisincardiomyopathycausedbymutationsinthelaminacgene AT vigniern erk12directlyactsonctgfccn2expressiontomediatemyocardialfibrosisincardiomyopathycausedbymutationsinthelaminacgene AT mougenotn erk12directlyactsonctgfccn2expressiontomediatemyocardialfibrosisincardiomyopathycausedbymutationsinthelaminacgene AT bonneg erk12directlyactsonctgfccn2expressiontomediatemyocardialfibrosisincardiomyopathycausedbymutationsinthelaminacgene AT lipsonk erk12directlyactsonctgfccn2expressiontomediatemyocardialfibrosisincardiomyopathycausedbymutationsinthelaminacgene AT wormanh erk12directlyactsonctgfccn2expressiontomediatemyocardialfibrosisincardiomyopathycausedbymutationsinthelaminacgene AT muchira erk12directlyactsonctgfccn2expressiontomediatemyocardialfibrosisincardiomyopathycausedbymutationsinthelaminacgene |