Endothelial apoptosis in pulmonary hypertension is controlled by a microRNA/programmed cell death 4/caspase-3 axis

Kevin White, Yvonne Dempsie, Paola Caruso, Emma Wallace, Robert A. McDonald, Hannah Stevens, Mark E. Hatley, Eva Van Rooij, Nicholas W. Morrell, Margaret R. Maclean, Andrew H. Baker

Research output: Contribution to journalArticle

48 Citations (Scopus)

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 -/- 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 -/- 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.

Original languageEnglish
Pages (from-to)185-194
Number of pages10
JournalHypertension
Volume64
Issue number1
DOIs
Publication statusPublished - 1 Jul 2014

Fingerprint

MicroRNAs
Pulmonary Hypertension
Caspase 3
Cell Death
Apoptosis
Lung
Endothelial Cells
Vascular Diseases
Knockout Mice
Lung Diseases
Wounds and Injuries

Keywords

  • apoptosis
  • endothelium
  • pulmonary hypertension
  • microRNAs
  • PDCD4 protein, human

Cite this

White, K., Dempsie, Y., Caruso, P., Wallace, E., McDonald, R. A., Stevens, H., ... Baker, A. H. (2014). Endothelial apoptosis in pulmonary hypertension is controlled by a microRNA/programmed cell death 4/caspase-3 axis. Hypertension, 64(1), 185-194. https://doi.org/10.1161/HYPERTENSIONAHA.113.03037
White, Kevin ; Dempsie, Yvonne ; Caruso, Paola ; Wallace, Emma ; McDonald, Robert A. ; Stevens, Hannah ; Hatley, Mark E. ; Van Rooij, Eva ; Morrell, Nicholas W. ; Maclean, Margaret R. ; Baker, Andrew H. / Endothelial apoptosis in pulmonary hypertension is controlled by a microRNA/programmed cell death 4/caspase-3 axis. In: Hypertension. 2014 ; Vol. 64, No. 1. pp. 185-194.
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White, K, Dempsie, Y, Caruso, P, Wallace, E, McDonald, RA, Stevens, H, Hatley, ME, Van Rooij, E, Morrell, NW, Maclean, MR & Baker, AH 2014, 'Endothelial apoptosis in pulmonary hypertension is controlled by a microRNA/programmed cell death 4/caspase-3 axis', Hypertension, vol. 64, no. 1, pp. 185-194. https://doi.org/10.1161/HYPERTENSIONAHA.113.03037

Endothelial apoptosis in pulmonary hypertension is controlled by a microRNA/programmed cell death 4/caspase-3 axis. / White, Kevin; Dempsie, Yvonne; Caruso, Paola; Wallace, Emma; McDonald, Robert A.; Stevens, Hannah; Hatley, Mark E.; Van Rooij, Eva; Morrell, Nicholas W.; Maclean, Margaret R.; Baker, Andrew H.

In: Hypertension, Vol. 64, No. 1, 01.07.2014, p. 185-194.

Research output: Contribution to journalArticle

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T1 - Endothelial apoptosis in pulmonary hypertension is controlled by a microRNA/programmed cell death 4/caspase-3 axis

AU - White, Kevin

AU - Dempsie, Yvonne

AU - Caruso, Paola

AU - Wallace, Emma

AU - McDonald, Robert A.

AU - Stevens, Hannah

AU - Hatley, Mark E.

AU - Van Rooij, Eva

AU - Morrell, Nicholas W.

AU - Maclean, Margaret R.

AU - Baker, Andrew H.

PY - 2014/7/1

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N2 - 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 -/- 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 -/- 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.

AB - 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 -/- 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 -/- 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.

KW - apoptosis

KW - endothelium

KW - pulmonary hypertension

KW - microRNAs

KW - PDCD4 protein, human

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White K, Dempsie Y, Caruso P, Wallace E, McDonald RA, Stevens H et al. Endothelial apoptosis in pulmonary hypertension is controlled by a microRNA/programmed cell death 4/caspase-3 axis. Hypertension. 2014 Jul 1;64(1):185-194. https://doi.org/10.1161/HYPERTENSIONAHA.113.03037