Endothelial indoleamine 2,3-dioxygenase protects against development of pulmonary hypertension.

Abstract

RATIONALE:

A proliferative and apoptosis-resistant phenotype in pulmonary arterial smooth muscle cells (PASMCs) is key to pathologic vascular remodeling in pulmonary hypertension (PH). Expression of indoleamine-2,3-dioxygenase (IDO) by vascular endothelium is a newly identified vasomotor-regulatory mechanism also involved in molecular signaling cascades governing vascular smooth muscle cell (vSMC) plasticity.

OBJECTIVES:

To investigate the therapeutic potential of enhanced endothelial IDO in development of PH and its associated vascular remodeling.

METHODS:

We used loss and gain of function in vivo studies to establish the role and determine the therapeutic effect of endothelial IDO in hypoxia-induced PH in mice and monocrotaline-induced PH in rats. We also studied PASMC phenotype in an IDO-high in vivo and in vitro tissue microenvironment.

MEASUREMENTS AND MAIN RESULTS:

The endothelium was the primary site for endogenous IDO production within mouse lung, and the mice lacking this gene had exaggerated hypoxia-induced PH. Conversely, augmented pulmonary endothelial IDO expression, through a human IDO-encoding Sleeping Beauty (SB)-based nonviral gene-integrating approach, halted and attenuated the development of PH, right ventricular hypertrophy, and vascular remodeling in both preclinical models of PH. IDO derived from endothelial cells promoted apoptosis in PH-PASMCs through depolarization of mitochondrial transmembrane potential and down-regulated PH-PASMC proliferative/synthetic capacity through enhanced binding of myocardin to CArG box DNA sequences present within the promoters of vSMC differentiation-specific genes.

CONCLUSIONS:

Enhanced endothelial IDO ameliorates PH and its associated vascular structural remodeling through paracrine phenotypic modulation of PH-PASMCs toward a proapoptotic and less proliferative/synthetic state.

• Authors: Yongguang Xiao, Helen Christou, Li Liu, Gary Visner, S Alex Mitsialis, Stella Kourembanas, Hanzhong Liu
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 188 Issue 4 Pg. 482-91 (Aug 15 2013) ISSN: 1535-4970 [Electronic] United States
• PMID: 23822766 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Transposable Elements
• Elk1 protein, mouse
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• ets-Domain Protein Elk-1

Topics

• Animals
• Apoptosis
• Cell Proliferation
• Cells, Cultured
• DNA Transposable Elements
• Endothelium, Vascular (metabolism)
• Hypertension, Pulmonary (enzymology, prevention & control)
• Indoleamine-Pyrrole 2,3,-Dioxygenase (biosynthesis)
• Lung (enzymology)
• Mice
• Myocytes, Smooth Muscle (metabolism)
• Rats
• Up-Regulation
• ets-Domain Protein Elk-1 (physiology)