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Angiotensin blockade inhibits SIF DNA binding activities via STAT3 after myocardial infarction
T Omura1, M Yoshiyama, K Takeuchi
1First Department of Internal Medicine, Osaka City University Medical School, Osaka, Japan.
Insights
Myocardial infarction activates signal transducer and activator of transcription 3 (STAT3) in the heart. Angiotensin blockade with imidapril or candesartan cilexitil inhibited this STAT3 activation, suggesting a role in cardiac remodeling.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Gene Regulation
Background:
- Transcription factor activation is crucial for cellular regulation but poorly understood in myocardial infarction.
- The signal transducer and activator of transcription (STAT) pathway's role in infarcted hearts requires further investigation.
Purpose of the Study:
- To investigate STAT pathway activation, specifically as sis-inducing factor (SIF), in myocardial infarction.
- To evaluate the impact of angiotensin blockade on SIF activity in both ischemic and non-ischemic heart regions.
Main Methods:
- Myocardial infarction induced by coronary artery ligation in Wistar rats.
- Electrophoretic mobility shift assay (EMSA) to assess SIF DNA binding activity.
- Immunoprecipitation-Western blot to detect STAT3 tyrosine phosphorylation.
Main Results:
- SIF DNA binding activity increased significantly in both infarcted and non-infarcted myocardium post-myocardial infarction, peaking at 1 week.
- STAT3 proteins were identified within the increased SIF DNA complex, with elevated tyrosine phosphorylation observed at 1 week.
- Imidapril and candesartan cilexitil effectively suppressed the rise in SIF DNA binding activity and STAT3 phosphorylation.
Conclusions:
- Myocardial infarction leads to STAT3 activation in the heart.
- Angiotensin II type 1 (AT1) receptor signaling appears to partially mediate STAT3 transcriptional activation, contributing to cardiac remodeling post-myocardial infarction.
Abstract:
The in vivo activation of transcription factors, which is important for cell regulation by gene expression, has not been well examined in myocardial infarcted heart. The purpose of this study was to determine whether myocardial signal transducer and activator of transcription (STAT) pathway is activated as sis-inducing factor (SIF) in infarcted heart, and to assess the angiotensin blockade on SIF activity in ischemic and non-ischemic myocardium of rat. Myocardial infarction was made by ligation of the coronary artery in Wistar rats. In electrophoretic mobility shift assay, myocardial SIF DNA binding activities gradually increased and reached to peak at 1 week in infarcted and non-infarcted regions after myocardial infarction. Imidapril and candesartan cilexitil significantly prevented the increase in SIF DNA binding activity in infarcted and non-infarcted regions. This increased SIF DNA complex was supershifted by specific anti-STAT3 antibody, indicating that increased SIF complex at least contained activated STAT3 proteins in myocardial infarcted heart. Furthermore, immunoprecipitation-Western blot analysis revealed that STAT3 of infarcted and non-infarcted regions were tyrosine-phosphorylated at 1 week after myocardial infarction. Imidapril and candesartan cilexitil prevented the increase in phosphorylated STAT3. Thus, the transcriptional activation of STAT3 through AT1 receptor may be partially involved in cardiac remodeling after myocardial infarction.