© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
The functional role of the JAK–STAT pathway in post-infarction remodeling
aNew York Harbor VA Healthcare System, Brooklyn Campus, Brooklyn, NY 11209, USA
bDepartment of Medicine, State University of New York, Downstate Medical Center, Box 1199, 450 Clarkson Avenue, Brooklyn, NY 11203, USA
cDepartment of Anatomy and Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA
* Corresponding author. Tel.: +1-718-270-4147; fax: +1-718-630-3740. nelsherif{at}aol.com
Objectives: Recently, the Janus kinase/signal transducer and activator of transcription (JAK–STAT) signaling pathway was found to be prominently associated with activation of the autocrine loop of the heart tissue-localized renin angiotensin system (RAS). We investigated if the JAK–STAT pathway is activated in the post-myocardial infarction (MI) non-ischemic myocardium (NIM), destined to undergo remodeling and whether blockade of the pathway in vivo can modify early post-MI remodeling. Methods: We investigated the time course of tyrosine phosphorylation of JAK–STAT and gp130 proteins in the NIM of post-MI rat heart as well as the binding activity of STAT proteins to the St-domain of the angiotensinogen gene promoter. We further compared the effects of in vivo blockade of RAS by the AT1 receptor (AT1R) blocker losartan with the in vivo blockade of JAK–STAT pathway by the specific JAK2 blocker tyrphostin AG490 on certain aspects of early post-MI remodeling. Results: We showed that JAK2, STATs 1, 3, 5a and 6 and gp130 proteins are tyrosine phosphorylated as early as 5–30 min post-MI and that STATs 1, 3, and 5a remain activated up to 7 days post-MI. Gel mobility shift assay showed a strong binding activity of STAT proteins to the St-domain of angiotensinogen gene promoter in 1-day post-MI NIM. The binding was significantly reduced in rat hearts previously treated with losartan or tyrphostin AG490. Supershift experiments identified STATs 3 and 5a as specifically interacting with the St-domain. Both AT1R and JAK2 blockade resulted in significant amelioration of the increase of protein phosphatase 1 activity and decrease in basal level of p16-phospholamban that may underlie early diastolic dysfunction, as well as partial amelioration of early downregulation of Kv4.2 gene expression that may underlie increased arrhythmogenicity of 3-day post-MI heart. On the other hand, while blockade of AT1R significantly ameliorated apoptotic changes in 1-day post-MI border zone, blockade of JAK2 increased apoptosis. Conclusions: The study provides compelling evidence in favor of the linkage of the JAK–STAT pathway with the angiotensin II autocrine loop and uncovers a mechanism by which selective activation of a set of STAT proteins underlies mobilization of the gene activation program intrinsic to post-MI remodeling. It also suggests that drugs that inhibit JAK–STAT phosphorylation may provide a new approach to modify post-MI remodeling. This needs to be confirmed in long term in vivo studies in the post-MI heart.
KEYWORDS Apoptosis; Infarction; Remodeling; Renin angiotensin system; Signal transduction
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