Effects of irbesartan on gene expression revealed by transcriptome analysis of left atrial tissue in a porcine model of acute rapid pacing in vivo.

Abstract

BACKGROUND:

Atrial fibrillation (AF) is characterized by electrical and structural remodeling of the atria with atrial fibrosis being one hallmark. Angiotensin II (AngII) is a major contributing factor and blockage of its type I receptor (AT1R) prevents remodeling to some extent. Here we explored the effects of the AT1R antagonist irbesartan on global gene expression and profibrotic signaling pathways after induction of rapid atrial pacing (RAP) in vivo in pigs.

METHODS AND RESULTS:

Microarray-based RNA profiling was used to screen left atrial (LA) tissue specimens for differences in atrial gene expression in a model of acute RAP. RAP caused an overall expression profile that reflected AngII-induced ROS production, tissue remodeling, and energy depletion. Of special note, the mRNA levels of EDN1, SGK1, and CTGF encoding pro-endothelin, stress- and glucocorticoid activated kinase-1, and of connective tissue growth factor were identified to be significantly increased after 7h of rapid pacing. These specific expression changes were additionally validated by RT-qPCR or immunoblot analyses in LA, RA, and partly in LV samples. All RAP-induced differential gene expression patterns were partially attenuated in the presence of irbesartan. Similar results were obtained after RAP of HL-1 cardiomyocytes in vitro. Furthermore, exogenously added endothelin-1 (ET1) induced CTGF expression concomitant to the transcriptional activation of SGK1 in HL-1 cells.

CONCLUSIONS:

RAP provokes substantial changes in atrial and ventricular myocardial gene expression that could be partly reversed by irbesartan. ET1 contributes to AF-dependent atrial fibrosis by synergistic activity with AngII to stimulate SGK1 expression and enhance phosphorylation of the SGK1 protein which, in turn, induces CTGF. The latter has been consistently associated with tissue fibrosis. These findings suggest ETR antagonists as being beneficial in AF treatment.

• Authors: Ravi Kumar Chilukoti, Jörg Mostertz, Alicja Bukowska, Christoph Aderkast, Stephan B Felix, Matthias Busch, Uwe Völker, Andreas Goette, Carmen Wolke, Georg Homuth, Uwe Lendeckel
• Journal: International journal of cardiology (Int J Cardiol) Vol. 168 Issue 3 Pg. 2100-8 (Oct 03 2013) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 23414741 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Biphenyl Compounds
• RNA, Messenger
• Tetrazoles
• Angiotensin II
• Connective Tissue Growth Factor
• Irbesartan

Topics

• Angiotensin II
• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Animals
• Atrial Fibrillation (drug therapy, genetics, physiopathology)
• Biphenyl Compounds (pharmacology)
• Blotting, Western
• Cell Line
• Connective Tissue Growth Factor (biosynthesis, genetics)
• Disease Models, Animal
• Gene Expression Profiling (methods)
• Gene Expression Regulation (drug effects)
• Heart Atria (drug effects, metabolism, pathology)
• Heart Rate
• Irbesartan
• Mice
• Microarray Analysis
• Myocytes, Cardiac (metabolism, pathology)
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Swine
• Tetrazoles (pharmacology)