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.
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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)
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Chemical References |
- DNA Transposable Elements
- Elk1 protein, mouse
- Indoleamine-Pyrrole 2,3,-Dioxygenase
- ets-Domain Protein Elk-1
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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)
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