Fibronectin gene expression in aortic regurgitation: relative roles of mitogen-activated protein kinases.
OBJECTIVE
In aortic regurgitation (AR), fibronectin (FN) expression is upregulated. This study sought to determine signal transduction pathways involved in upregulation of FN expression in AR.


METHODS
Cardiac fibroblasts (CF) from rabbits with surgically induced AR and matched controls (NL) were cultured and assayed for FN expression and kinase activity with and without inhibitors of kinases JNK, p38 mitogen-activated protein kinase (MAPK) and extracellular response kinase (ERK). NL CF also were subjected to cyclic strain mimicking AR for 24 h in culture with and without inhibitors.


RESULTS
AR CF exhibited 2.9-fold greater c-Jun phosphorylation (p < 0.01) and 1.5- to 2-fold greater ATF2 phosphorylation (p < 0.05-0.01) than NL. JNK and p38MAPK inhibition reduced c-Jun and ATF2 phosphorylation to NL; ERK inhibition had no effect. FN mRNA expression was similar in pattern to kinase activities. Cyclic strain in NL CF increased c-Jun phosphorylation 2-fold versus unstrained controls (p < 0.005). This was suppressed by inhibition of JNK but not p38MAPK.


CONCLUSIONS
FN expression in response to the acute mechanical strain resembling AR is upregulated primarily via JNK. However, in chronic AR both JNK and p38MAPK are involved. These signaling pathways represent potential therapeutic targets for normalizing extracellular matrix (ECM) composition and contractile force transmission, believed to be related to ECM composition/organization, in AR.
Truter
Sharada L
SL
Wyeth Research, Collegeville, PA, USA.
Catanzaro
Daniel F
DF
Supino
Phyllis G
PG
Gupta
Anuj
A
Carter
John
J
Ene
Ada R
AR
Herrold
Edmund M
EM
Dumlao
Themy F
TF
Beltran
Frans
F
Borer
Jeffrey S
JS
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D001022:Aortic Valve Insufficiency / Q000378:metabolism* / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D013314:Stress, Mechanical; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D051698:Activating Transcription Factor 2; D004791:Enzyme Inhibitors; D005353:Fibronectins; D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases