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  miR-223-IGF-IR signalling in hypoxia- and load-induced right-ventricular failure: a novel therapeutic approach

Shi, L., Kojonazarov, B., Elgheznawy, A., Popp, R., Dahal, B. K., Boehm, M., et al. (2016). miR-223-IGF-IR signalling in hypoxia- and load-induced right-ventricular failure: a novel therapeutic approach. CARDIOVASCULAR RESEARCH, 111(3), 184-193. doi:10.1093/cvr/cvw065.

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 Creators:
Shi, Lei, Author
Kojonazarov, Baktybek, Author
Elgheznawy, Amro, Author
Popp, Ruediger, Author
Dahal, Bhola Kumar, Author
Boehm, Mario, Author
Pullamsetti, Soni Savai1, Author           
Ghofrani, Hossein-Ardeschir, Author
Goedecke, Axel, Author
Jungmann, Andreas, Author
Katus, Hugo A., Author
Mueller, Oliver J., Author
Schermuly, Ralph T., Author
Fisslthaler, Beate, Author
Seeger, Werner1, Author           
Fleming, Ingrid, Author
Affiliations:
1Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              

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Free keywords: PULMONARY ARTERIAL-HYPERTENSION; BREAST-CANCER; MICRORNA; EXPRESSION; GENE; HEART; ANGIOGENESIS; RECEPTOR; CELLS; LUNGCardiovascular System & Cardiology; Hypertension; Pulmonary; Hypoxia; Pulmonary heart disease;
 Abstract: Pulmonary hypertension is a progressive disease with poor prognosis, characterized by pathological inward remodelling and loss of patency of the lung vasculature. The right ventricle is co-affected by pulmonary hypertension, which triggers events such as hypoxia and/or increased mechanical load. Initially the right ventricle responds with 'adaptive' hypertrophy, which is often rapidly followed by 'maladaptive' changes leading to right heart decompensation and failure, which is the ultimate cause of death. We report here that miR-223 is expressed in the murine lung and right ventricle at higher levels than in the left ventricle. Moreover, lung and right-ventricular miR-223 levels were markedly down-regulated by hypoxia. Correspondingly, increasing right-ventricular load by pulmonary artery banding, induced right-ventricular ischaemia, and the down-regulation of miR-223. Lung and right ventricle miR-223 down-regulation were linked with increased expression of the miR-223 target; insulin-like growth factor-I receptor (IGF-IR) and IGF-I downstream signalling. Similarly, miR-223 was decreased and IGF-IR increased in human pulmonary hypertension. Notably in young mice, miR-223 overexpression, the genetic inactivation or pharmacological inhibition of IGF-IR, all attenuated right-ventricular hypertrophy and improved right heart function under conditions of hypoxia or increased afterload. These findings highlight the early role of pulmonary and right-ventricular miR-223 and the IGF-IR in the right heart failure programme initiated by pulmonary hypoxia and increased mechanical load and may lead to the development of novel therapeutic strategies that target the development of PH and right heart failure.

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Language(s): eng - English
 Dates: 2016
 Publication Status: Published in print
 Pages: 10
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000383197000006
DOI: 10.1093/cvr/cvw065
 Degree: -

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Title: CARDIOVASCULAR RESEARCH
Source Genre: Journal
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Publ. Info: GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND : OXFORD UNIV PRESS
Pages: - Volume / Issue: 111 (3) Sequence Number: - Start / End Page: 184 - 193 Identifier: ISSN: 0008-6363