(Pro)renin receptor triggers distinct angiotensin II-independent extracellular matrix remodeling and deterioration of cardiac function.

<h4>Background</h4>Activation of the renin-angiotensin-system (RAS) plays a key pathophysiological role in heart failure in patients with hypertension and myocardial infarction. However, the function of (pro)renin receptor ((P)RR) is not yet solved. We determined here the direct function...

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Autores principales:	Anne-Mari Moilanen, Jaana Rysä, Raisa Serpi, Erja Mustonen, Zoltán Szabò, Jani Aro, Juha Näpänkangas, Olli Tenhunen, Meeri Sutinen, Tuula Salo, Heikki Ruskoaho
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/62daa18b1bda4fc68426b9d44b6eae67
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spelling	oai:doaj.org-article:62daa18b1bda4fc68426b9d44b6eae672021-11-18T07:11:26Z(Pro)renin receptor triggers distinct angiotensin II-independent extracellular matrix remodeling and deterioration of cardiac function.1932-620310.1371/journal.pone.0041404https://doaj.org/article/62daa18b1bda4fc68426b9d44b6eae672012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22911790/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Activation of the renin-angiotensin-system (RAS) plays a key pathophysiological role in heart failure in patients with hypertension and myocardial infarction. However, the function of (pro)renin receptor ((P)RR) is not yet solved. We determined here the direct functional and structural effects of (P)RR in the heart.<h4>Methodology/principal findings</h4>(P)RR was overexpressed by using adenovirus-mediated gene delivery in normal adult rat hearts up to 2 weeks. (P)RR gene delivery into the anterior wall of the left ventricle decreased ejection fraction (P<0.01), fractional shortening (P<0.01), and intraventricular septum diastolic and systolic thickness, associated with approximately 2-fold increase in left ventricular (P)RR protein levels at 2 weeks. To test whether the worsening of cardiac function and structure by (P)RR gene overexpression was mediated by angiotensin II (Ang II), we infused an AT(1) receptor blocker losartan via osmotic minipumps. Remarkably, cardiac function deteriorated in losartan-treated (P)RR overexpressing animals as well. Intramyocardial (P)RR gene delivery also resulted in Ang II-independent activation of extracellular-signal-regulated kinase1/2 phosphorylation and myocardial fibrosis, and the expression of transforming growth factor-β1 and connective tissue growth factor genes. In contrast, activation of heat shock protein 27 phosphorylation and apoptotic cell death by (P)RR gene delivery was Ang II-dependent. Finally, (P)RR overexpression significantly increased direct protein-protein interaction between (P)RR and promyelocytic zinc-finger protein.<h4>Conclusions/significance</h4>These results indicate for the first time that (P)RR triggers distinct Ang II-independent myocardial fibrosis and deterioration of cardiac function in normal adult heart and identify (P)RR as a novel therapeutic target to optimize RAS blockade in failing hearts.Anne-Mari MoilanenJaana RysäRaisa SerpiErja MustonenZoltán SzabòJani AroJuha NäpänkangasOlli TenhunenMeeri SutinenTuula SaloHeikki RuskoahoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 7, p e41404 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anne-Mari Moilanen Jaana Rysä Raisa Serpi Erja Mustonen Zoltán Szabò Jani Aro Juha Näpänkangas Olli Tenhunen Meeri Sutinen Tuula Salo Heikki Ruskoaho (Pro)renin receptor triggers distinct angiotensin II-independent extracellular matrix remodeling and deterioration of cardiac function.
description	<h4>Background</h4>Activation of the renin-angiotensin-system (RAS) plays a key pathophysiological role in heart failure in patients with hypertension and myocardial infarction. However, the function of (pro)renin receptor ((P)RR) is not yet solved. We determined here the direct functional and structural effects of (P)RR in the heart.<h4>Methodology/principal findings</h4>(P)RR was overexpressed by using adenovirus-mediated gene delivery in normal adult rat hearts up to 2 weeks. (P)RR gene delivery into the anterior wall of the left ventricle decreased ejection fraction (P<0.01), fractional shortening (P<0.01), and intraventricular septum diastolic and systolic thickness, associated with approximately 2-fold increase in left ventricular (P)RR protein levels at 2 weeks. To test whether the worsening of cardiac function and structure by (P)RR gene overexpression was mediated by angiotensin II (Ang II), we infused an AT(1) receptor blocker losartan via osmotic minipumps. Remarkably, cardiac function deteriorated in losartan-treated (P)RR overexpressing animals as well. Intramyocardial (P)RR gene delivery also resulted in Ang II-independent activation of extracellular-signal-regulated kinase1/2 phosphorylation and myocardial fibrosis, and the expression of transforming growth factor-β1 and connective tissue growth factor genes. In contrast, activation of heat shock protein 27 phosphorylation and apoptotic cell death by (P)RR gene delivery was Ang II-dependent. Finally, (P)RR overexpression significantly increased direct protein-protein interaction between (P)RR and promyelocytic zinc-finger protein.<h4>Conclusions/significance</h4>These results indicate for the first time that (P)RR triggers distinct Ang II-independent myocardial fibrosis and deterioration of cardiac function in normal adult heart and identify (P)RR as a novel therapeutic target to optimize RAS blockade in failing hearts.
format	article
author	Anne-Mari Moilanen Jaana Rysä Raisa Serpi Erja Mustonen Zoltán Szabò Jani Aro Juha Näpänkangas Olli Tenhunen Meeri Sutinen Tuula Salo Heikki Ruskoaho
author_facet	Anne-Mari Moilanen Jaana Rysä Raisa Serpi Erja Mustonen Zoltán Szabò Jani Aro Juha Näpänkangas Olli Tenhunen Meeri Sutinen Tuula Salo Heikki Ruskoaho
author_sort	Anne-Mari Moilanen
title	(Pro)renin receptor triggers distinct angiotensin II-independent extracellular matrix remodeling and deterioration of cardiac function.
title_short	(Pro)renin receptor triggers distinct angiotensin II-independent extracellular matrix remodeling and deterioration of cardiac function.
title_full	(Pro)renin receptor triggers distinct angiotensin II-independent extracellular matrix remodeling and deterioration of cardiac function.
title_fullStr	(Pro)renin receptor triggers distinct angiotensin II-independent extracellular matrix remodeling and deterioration of cardiac function.
title_full_unstemmed	(Pro)renin receptor triggers distinct angiotensin II-independent extracellular matrix remodeling and deterioration of cardiac function.
title_sort	(pro)renin receptor triggers distinct angiotensin ii-independent extracellular matrix remodeling and deterioration of cardiac function.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/62daa18b1bda4fc68426b9d44b6eae67
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(Pro)renin receptor triggers distinct angiotensin II-independent extracellular matrix remodeling and deterioration of cardiac function.

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