White, K, Dempsie, Y, Caruso, P, Wallace, E, McDonald, RA, Stevens, H, Hatley, ME, Van, RE, Morrell, NW, Maclean, MR and Baker, AH (2014) Endothelial apoptosis in pulmonary hypertension is controlled by a microRNA/programmed cell death 4/caspase-3 axis. Hypertension. pp. 185-194.

Abstract

Pulmonary endothelial cell apoptosis is a transient, yet defining pathogenic event integral to the onset of many pulmonary vascular diseases such as pulmonary hypertension (PH). However, there is a paucity of information concerning the molecular pathway(s) that control pulmonary arterial endothelial cell apoptosis. Here, we introduce a molecular axis that when functionally active seems to induce pulmonary arterial endothelial cell apoptosis in vitro and PH in vivo. In response to apoptotic stimuli, human pulmonary arterial endothelial cells exhibited robust induction of a programmed cell death 4 (PDCD4)/caspase-3/apoptotic pathway that was reversible by direct PDCD4 silencing. Indirectly, this pathway was also repressed by delivery of a microRNA-21 mimic. In vivo, genetic deletion of microRNA-21 in mice (miR-21 <sup>-/-</sup> mice) resulted in functional activation of the PDCD4/caspase-3 axis in the pulmonary tissues, leading to the onset of progressive PH. Conversely, microRNA-21-overexpressing mice (CAG-microRNA-21 mice) exhibited reduced PDCD4 expression in pulmonary tissues and were partially resistant to PH in response to chronic hypoxia plus SU 5416 injury. Furthermore, direct PDCD4 knockout in mice (PDCD4<sup>-/-</sup> mice) potently blocked pulmonary caspase-3 activation and the development of chronic hypoxia plus SU 5416 PH, confirming its importance in disease onset. Broadly, these findings support the existence of a microRNA-21-responsive PDCD4/caspase-3 pathway in the pulmonary tissues that when active serves to promote endothelial apoptosis in vitro and PH in vivo. 2014 American Heart Association, Inc

Item Type:	Article
Additional Information:	NIBR author: institute: NIBR contributor address: (White, Dempsie, Caruso, Wallace, McDonald, Stevens, Maclean, Baker) Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom (Hatley) Solid Tumor Division, St. Jude Children's Research Hospital, Memphis, TN, United States (Van Rooij) MiRagen Therapeutics, Boulder, CO, United States (Morrell) Division of Respiratory Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom (White) Novartis Institutes for Biomedical Research, Horsham, United Kingdom (Dempsie) School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, United Kingdom (Caruso) Department of Medicine, University of Cambridge, School of Clinical Medicine, Cambridge, United Kingdom (Van Rooij) Hubrecht Institute, Utrecht, Netherlands
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/22756