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 1R) 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 determined whether miRNAs might be regulated by AT 1R signals in a Gαq/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 overexpressing the AT 1R and focused on separating the role of Gαq/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 up-regulated by Ang II in HEK293N cells. In contrast, the biased Ang II analogue, [Sar1, Ile4, Ile8] Ang II (SII Ang II), which selectively activates Gαq/11-independent signalling, failed to regulate miRNAs in HEK293N cells. Furthermore, Ang II-induced miRNA regulation was blocked following Gαq/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 down-regulated miR-129-3p. CONCLUSIONS AND IMPLICATIONS Five miRNAs were regulated by Ang II through mechanisms depending on Gαq/11 and Erk1/2 activation. These miRNAs may be involved in Ang II-mediated cardiac biology and disease, as several of these miRNAs have previously been associated with cardiovascular disease and were found to be regulated in cardiac cells.
AB - BACKGROUND AND PURPOSE The angiotensin II type 1 receptor (AT 1R) 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 determined whether miRNAs might be regulated by AT 1R signals in a Gαq/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 overexpressing the AT 1R and focused on separating the role of Gαq/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 up-regulated by Ang II in HEK293N cells. In contrast, the biased Ang II analogue, [Sar1, Ile4, Ile8] Ang II (SII Ang II), which selectively activates Gαq/11-independent signalling, failed to regulate miRNAs in HEK293N cells. Furthermore, Ang II-induced miRNA regulation was blocked following Gαq/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 down-regulated miR-129-3p. CONCLUSIONS AND IMPLICATIONS Five miRNAs were regulated by Ang II through mechanisms depending on Gαq/11 and Erk1/2 activation. These miRNAs may be involved in Ang II-mediated cardiac biology and disease, as several of these miRNAs have previously been associated with 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
SN - 0007-1188
VL - 164
SP - 394
EP - 404
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 2
ER -
