A Critical Role for the Protein Apoptosis Repressor With Caspase Recruitment Domain in Hypoxia-Induced Pulmonary Hypertension

Pulmonary hypertension (PH) is a lethal syndrome associated with the pathogenic remodeling of the pulmonary vasculature and the emergence of apoptosis-resistant cells. Apoptosis repressor with caspase recruitment domain (ARC) is an inhibitor of multiple forms of cell death known to be abundantly exp...

Full description

Saved in:
Bibliographic Details
Published in:Circulation (New York, N.Y.) N.Y.), 2011-12, Vol.124 (23), p.2533-2542
Main Authors: ZAIMAN, Ari L, DAMICO, Rachel, EL-HADDAD, Hazim, SHIMODA, Larissa A, PENG, Chang-Fu, HASSOUN, Paul M, CHAMPION, Hunter C, KITSIS, Richard N, CROW, Michael T, THOMS-CHESLEY, Alan, CLARK FILES, D, KESARI, Priya, JOHNSTON, Laura, SWAIM, Mara, MOZAMMEL, Shehzin, MYERS, Alan C, HALUSHKA, Marc
Format: Article
Language:English
Subjects:
Animals
Apoptosis Regulatory Proteins - genetics
Apoptosis Regulatory Proteins - metabolism
Biological and medical sciences
Blood and lymphatic vessels
Cardiology. Vascular system
Cell Death - physiology
Cell Division - physiology
Cells, Cultured
Chronic Disease
Disease Models, Animal
Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous
Humans
Hypertension, Pulmonary - metabolism
Hypertension, Pulmonary - pathology
Hypertension, Pulmonary - physiopathology
Hypoxia - metabolism
Hypoxia - pathology
Hypoxia - physiopathology
Medical sciences
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle Proteins - genetics
Muscle Proteins - metabolism
Muscle, Smooth, Vascular - cytology
Muscle, Smooth, Vascular - physiology
Pneumology
Potassium Channels, Voltage-Gated - genetics
Potassium Channels, Voltage-Gated - physiology
Pulmonary Circulation - physiology
Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases
Rats
Up-Regulation - physiology
Vasoconstriction - physiology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Pulmonary hypertension (PH) is a lethal syndrome associated with the pathogenic remodeling of the pulmonary vasculature and the emergence of apoptosis-resistant cells. Apoptosis repressor with caspase recruitment domain (ARC) is an inhibitor of multiple forms of cell death known to be abundantly expressed in striated muscle. We show for the first time that ARC is expressed in arterial smooth muscle cells of the pulmonary vasculature and is markedly upregulated in several experimental models of PH. In this study, we test the hypothesis that ARC expression is essential for the development of chronic hypoxia-induced PH. Experiments in which cells or mice were rendered ARC-deficient revealed that ARC not only protected pulmonary arterial smooth muscle cells from hypoxia-induced death, but also facilitated growth factor-induced proliferation and hypertrophy and hypoxia-induced downregulation of selective voltage-gated potassium channels, the latter a hallmark of the syndrome in humans. Moreover, ARC-deficient mice exhibited diminished vascular remodeling, increased apoptosis, and decreased proliferation in response to chronic hypoxia, resulting in marked protection from PH in vivo. Patients with PH have significantly increased ARC expression not only in remodeled vessels but also in the lumen-occluding lesions associated with severe disease. These data show that ARC, previously unlinked to pulmonary hypertension, is a critical determinant of vascular remodeling in this syndrome.
ISSN:0009-7322
1524-4539
DOI:10.1161/CIRCULATIONAHA.111.034512