The functional role of the JAK-STAT pathway in post-infarction remodeling.
OBJECTIVE
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 AT(1) receptor (AT(1)R) 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 AT(1)R 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 AT(1)R 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.
El-Adawi
Hala
H
New York Harbor VA Healthcare System, Brooklyn Campus, Brooklyn, NY 11209, USA.
Deng
Lili
L
Tramontano
Anthony
A
Smith
Steven
S
Mascareno
Eduardo
E
Ganguly
Kalyan
K
Castillo
Ricardo
R
El-Sherif
Nabil
N
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D019808:Losartan / Q000494:pharmacology; D008894:Milk Proteins; D023421:Models, Animal; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000502:physiology; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology; D020257:Ventricular Remodeling
D000889:Anti-Arrhythmia Agents; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D015221:Potassium Channels; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D020032:Tyrphostins; D000804:Angiotensin II; D011505:Protein-Tyrosine Kinases; C507906:Jak1 protein, rat; C507927:Jak2 protein, rat; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D019808:Losartan