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

Pia Lindgren Jeppesen; Gitte Lund Christensen; Mikael Schneider; Anne Yaël Nossent; Hasse Brønnum Jensen; Ditte Caroline Andersen; Tilde Eskildsen; Steen Gammeltoft; Jakob Lerche Hansen; Søren Paludan Sheikh

doi:10.1111/j.1476-5381.2011.01375.x

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

Pia Lindgren Jeppesen, Gitte Lund Christensen, Mikael Schneider, Anne Yaël Nossent, Hasse Brønnum Jensen, Ditte Caroline Andersen, Tilde Eskildsen, Steen Gammeltoft, Jakob Lerche Hansen, Søren Paludan Sheikh

Inflammation, Metabolism and Oxidation

45 Citations (Scopus)

Abstract

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.

Original language	English
Journal	British Journal of Pharmacology
Volume	164
Issue number	2
Pages (from-to)	394-404
Number of pages	11
ISSN	0007-1188
DOIs	https://doi.org/10.1111/j.1476-5381.2011.01375.x
Publication status	Published - Sept 2011

Keywords

Angiotensin II
Anthracenes
Butadienes
Extracellular Signal-Regulated MAP Kinases
Fibroblasts
GTP-Binding Protein alpha Subunits, Gq-G11
Gene Expression Profiling
Gene Expression Regulation
HEK293 Cells
Humans
Imidazoles
MicroRNAs
Myocytes, Cardiac
Nitriles
Pyridines
Receptor, Angiotensin, Type 1
Signal Transduction

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10.1111/j.1476-5381.2011.01375.x

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Jeppesen, P. L., Christensen, G. L., Schneider, M., Nossent, A. Y., Jensen, H. B., Andersen, D. C., Eskildsen, T., Gammeltoft, S., Hansen, J. L., & Sheikh, S. P. (2011). Angiotensin II type 1 receptor signalling regulates microRNA differentially in cardiac fibroblasts and myocytes. British Journal of Pharmacology, 164(2), 394-404. https://doi.org/10.1111/j.1476-5381.2011.01375.x

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title = "Angiotensin II type 1 receptor signalling regulates microRNA differentially in cardiac fibroblasts and myocytes",

abstract = "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.",

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author = "Jeppesen, {Pia Lindgren} and Christensen, {Gitte Lund} and Mikael Schneider and Nossent, {Anne Ya{\"e}l} and Jensen, {Hasse Br{\o}nnum} and Andersen, {Ditte Caroline} and Tilde Eskildsen and Steen Gammeltoft and Hansen, {Jakob Lerche} and Sheikh, {S{\o}ren Paludan}",

note = "{\textcopyright} 2011 The Authors. British Journal of Pharmacology {\textcopyright} 2011 The British Pharmacological Society.",

year = "2011",

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doi = "10.1111/j.1476-5381.2011.01375.x",

language = "English",

volume = "164",

pages = "394--404",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

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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

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 -

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

Abstract

Keywords

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