These authors contributed equally to this work.
Angiotensin II type 1 receptor signalling regulates microRNA differentially in cardiac fibroblasts and myocytes
Version of Record online: 22 AUG 2011
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society
British Journal of Pharmacology
Volume 164, Issue 2, pages 394–404, September 2011
How to Cite
Jeppesen, P. L., Christensen, G. L., Schneider, M., Nossent, A. Y., Jensen, H. B., Andersen, D. C., Eskildsen, T., Gammeltoft, S., Hansen, J. L. and Sheikh, S. P. (2011), Angiotensin II type 1 receptor signalling regulates microRNA differentially in cardiac fibroblasts and myocytes. British Journal of Pharmacology, 164: 394–404. doi: 10.1111/j.1476-5381.2011.01375.x
- Issue online: 22 AUG 2011
- Version of Record online: 22 AUG 2011
- Accepted manuscript online: 30 MAR 2011 07:37PM EST
- Received; 13 September 2010; Revised; 11 February 2011; Accepted; 9 March 2011
- angiotensin II;
- cell signalling;
- biased agonist
BACKGROUND AND PURPOSE The angiotensin II type 1 receptor (AT1R) 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 AT1R 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 AT1R 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.