TY - JOUR
T1 - Angiotensin II signaling up-regulates the immediate early transcription factor ATF3 in the left but not the right atrium
AU - Hasin, Tal
AU - Elhanani, Ofer
AU - Abassi, Zaid
AU - Hai, Tsonwin
AU - Aronheim, Ami
N1 - Funding Information:
The authors wish to thank to Drs. Guillemette G. for HEK-293-ATR cell line; Reiter I. for assistance with IHC; Izhak Kehat continuous support, and Ms Cohen A. for technical assistance. This work was supported by the Etai Sharon Z’’l Rambam-Atidim Fellowship Fund for Academic Excellence to Tal Hasin, by grant no. MH-6087-1 from the Chief Scientist office of the Ministry of Health, Israel to AA and by Grant no 2009179 from the United States-Israel Binational Science Foundation (BSF) to AA and T. Hai. 1
PY - 2011/3
Y1 - 2011/3
N2 - The atria respond to various pathological stimuli including pressure and volume overload with remodeling and dilatation. Dilatation of the left atrium is associated with atrial fibrillation. The mechanisms involved in chamber-specific hypertrophy are largely unknown. Angiotensin II is hypothesized to take part in mediating this response. ATF3 is an immediate early gene found at the receiving end of multiple stress and growth stimuli. Here we characterize ATF3 as a direct target gene for angiotensin II. ATF3 expression is regulated by angiotensin receptor-mediated signaling in vivo and in vitro at the transcriptional level. ATF3 induction is mediated by cooperation between both the AT1A and AT2 receptor subtypes. While AT2R blocker (PD123319) efficiently blocks ATF3 induction in response to angiotensin II injection, it results in an increase in blood pressure indicating that the effect of angiotensin II on ATF3 is independent of its effect on blood pressure. In contrast to adrenergic stimulation that induces ATF3 in all heart chambers, ATF3 induction in response to angiotensin II occurs primarily in the left chambers. We hypothesize that the activation of differential signaling pathways accounts for the chamber-specific induction of ATF3 expression in response to angiotensin II stimulation. Angiotensin II injection rapidly activates the EGFR-dependent pathways including ERK and PI3K-AKT in the left but not the right atrium. EGF receptor inhibitor (Gefitinib/Iressa) as well as the AKT inhibitor (Triciribine) significantly abrogates ATF3 induction by angiotensin II in the left chambers. Collectively, our data strongly place ATF3 as a unique nuclear protein target in response to angiotensin II stimulation in the atria. The spatial expression of ATF3 may add to the understanding of the signaling pathways involved in cardiac response to neuro-hormonal stimulation, and in particular to the understanding of left atrial-generated pathology such as atrial fibrillation.
AB - The atria respond to various pathological stimuli including pressure and volume overload with remodeling and dilatation. Dilatation of the left atrium is associated with atrial fibrillation. The mechanisms involved in chamber-specific hypertrophy are largely unknown. Angiotensin II is hypothesized to take part in mediating this response. ATF3 is an immediate early gene found at the receiving end of multiple stress and growth stimuli. Here we characterize ATF3 as a direct target gene for angiotensin II. ATF3 expression is regulated by angiotensin receptor-mediated signaling in vivo and in vitro at the transcriptional level. ATF3 induction is mediated by cooperation between both the AT1A and AT2 receptor subtypes. While AT2R blocker (PD123319) efficiently blocks ATF3 induction in response to angiotensin II injection, it results in an increase in blood pressure indicating that the effect of angiotensin II on ATF3 is independent of its effect on blood pressure. In contrast to adrenergic stimulation that induces ATF3 in all heart chambers, ATF3 induction in response to angiotensin II occurs primarily in the left chambers. We hypothesize that the activation of differential signaling pathways accounts for the chamber-specific induction of ATF3 expression in response to angiotensin II stimulation. Angiotensin II injection rapidly activates the EGFR-dependent pathways including ERK and PI3K-AKT in the left but not the right atrium. EGF receptor inhibitor (Gefitinib/Iressa) as well as the AKT inhibitor (Triciribine) significantly abrogates ATF3 induction by angiotensin II in the left chambers. Collectively, our data strongly place ATF3 as a unique nuclear protein target in response to angiotensin II stimulation in the atria. The spatial expression of ATF3 may add to the understanding of the signaling pathways involved in cardiac response to neuro-hormonal stimulation, and in particular to the understanding of left atrial-generated pathology such as atrial fibrillation.
KW - ATF3
KW - Angiotensin
KW - Left atrium
KW - Signal transduction
UR - http://www.scopus.com/inward/record.url?scp=79957894843&partnerID=8YFLogxK
U2 - 10.1007/s00395-010-0145-9
DO - 10.1007/s00395-010-0145-9
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AN - SCOPUS:79957894843
SN - 0300-8428
VL - 106
SP - 175
EP - 187
JO - Basic Research in Cardiology
JF - Basic Research in Cardiology
IS - 2
ER -
