TY - JOUR

T1 - Angiotensin II type 1 receptor signalling regulates microRNA differentially in cardiac fibroblasts and myocytes

AU - Jeppesen, Pia Lindgren

AU - Christensen, Gitte Lund

AU - Schneider, Mikael

AU - Nossent, Anne Yaël

AU - Jensen, Hasse Brønnum

AU - Andersen, Ditte Caroline

AU - Eskildsen, Tilde

AU - Gammeltoft, Steen

AU - Hansen, Jakob Lerche

AU - Sheikh, Søren Paludan

N1 - © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

PY - 2011/9

Y1 - 2011/9

N2 - Background and purpose: The Angiotensin II type 1 receptor (AT(1) R) is a key regulator of blood pressure and cardiac contractility and is profoundly involved in development of cardiac disease. Since several microRNAs (miRNAs) have been implicated in cardiac disease, we asked whether miRNAs might be regulated by AT(1) R signals in a Gaq/11 dependent or -independent manner. Experimental approach: We performed a global miRNA array analysis of angiotensin II (Ang II) mediated miRNA regulation in HEK293N cells over-expressing the AT(1) R and focused on separating the role of Gaq/11 -dependent and -independent pathways. MiRNA regulation was verified with quantitative PCR in both HEK293N cells and primary cardiac myocytes and fibroblasts. Key results: Our studies revealed five miRNAs (miR-29b, -129-3p, -132, -132* and -212) that were upregulated by Ang II in HEK293N cells. In contrast, the biased Ang II analogue, [Sar1, Ile4, Ile8] Ang II (SII Ang II), which selectively activates Gaq/11-independent signalling, failed to regulate miRNAs in HEK293N cells Furthermore, Ang II induced miRNA regulation was blocked following Gaq/11 and Mek1 inhibition. The observed Ang II regulation of miRNA was confirmed in primary cultures of adult cardiac fibroblasts. Interestingly, Ang II did not regulate miRNA expression in cardiac myocytes, but SII Ang II significantly downregulated miR-129-3p. Conclusions and implications: Five miRNAs were regulated by Ang II through mechanisms depending on Gaq/11 and Erk1/2 activation. The reported miRNAs may be involved in Ang II-mediated cardiac biology and disease, as several of these miRNAs have previously been related to cardiovascular disease and were found to be regulated in cardiac cells.

AB - Background and purpose: The Angiotensin II type 1 receptor (AT(1) R) is a key regulator of blood pressure and cardiac contractility and is profoundly involved in development of cardiac disease. Since several microRNAs (miRNAs) have been implicated in cardiac disease, we asked whether miRNAs might be regulated by AT(1) R signals in a Gaq/11 dependent or -independent manner. Experimental approach: We performed a global miRNA array analysis of angiotensin II (Ang II) mediated miRNA regulation in HEK293N cells over-expressing the AT(1) R and focused on separating the role of Gaq/11 -dependent and -independent pathways. MiRNA regulation was verified with quantitative PCR in both HEK293N cells and primary cardiac myocytes and fibroblasts. Key results: Our studies revealed five miRNAs (miR-29b, -129-3p, -132, -132* and -212) that were upregulated by Ang II in HEK293N cells. In contrast, the biased Ang II analogue, [Sar1, Ile4, Ile8] Ang II (SII Ang II), which selectively activates Gaq/11-independent signalling, failed to regulate miRNAs in HEK293N cells Furthermore, Ang II induced miRNA regulation was blocked following Gaq/11 and Mek1 inhibition. The observed Ang II regulation of miRNA was confirmed in primary cultures of adult cardiac fibroblasts. Interestingly, Ang II did not regulate miRNA expression in cardiac myocytes, but SII Ang II significantly downregulated miR-129-3p. Conclusions and implications: Five miRNAs were regulated by Ang II through mechanisms depending on Gaq/11 and Erk1/2 activation. The reported miRNAs may be involved in Ang II-mediated cardiac biology and disease, as several of these miRNAs have previously been related to cardiovascular disease and were found to be regulated in cardiac cells.

KW - Angiotensin II

KW - Anthracenes

KW - Butadienes

KW - Extracellular Signal-Regulated MAP Kinases

KW - Fibroblasts

KW - GTP-Binding Protein alpha Subunits, Gq-G11

KW - Gene Expression Profiling

KW - Gene Expression Regulation

KW - HEK293 Cells

KW - Humans

KW - Imidazoles

KW - MicroRNAs

KW - Myocytes, Cardiac

KW - Nitriles

KW - Pyridines

KW - Receptor, Angiotensin, Type 1

KW - Signal Transduction

U2 - 10.1111/j.1476-5381.2011.01375.x

DO - 10.1111/j.1476-5381.2011.01375.x

M3 - Journal article

C2 - 21449976

VL - 164

SP - 394

EP - 404

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 2

ER -