A critical role for the protein apoptosis repressor with caspase recruitment domain in hypoxia-induced pulmonary hypertension

Ari L. Zaiman, Rachel Damico, Alan Thoms-Chesley, D. Clark Files, Priya Kesari, Laura Johnston, Mara Swaim, Shehzin Mozammel, Alan C. Myers, Marc Halushka, Hazim El-Haddad, Larissa A. Shimoda, Chang Fu Peng, Paul M. Hassoun, Hunter C. Champion, Richard N. Kitsis, Michael T. Crow

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Background-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. Methods and Results-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. Conclusions-These data show that ARC, previously unlinked to pulmonary hypertension, is a critical determinant of vascular remodeling in this syndrome.

Original languageEnglish (US)
Pages (from-to)2533-2542
Number of pages10
JournalCirculation
Volume124
Issue number23
DOIs
Publication statusPublished - Dec 6 2011

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Keywords

  • apoptosis
  • hypertension
  • muscle
  • pulmonary
  • smooth

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Zaiman, A. L., Damico, R., Thoms-Chesley, A., Clark Files, D., Kesari, P., Johnston, L., ... Crow, M. T. (2011). A critical role for the protein apoptosis repressor with caspase recruitment domain in hypoxia-induced pulmonary hypertension. Circulation, 124(23), 2533-2542. https://doi.org/10.1161/CIRCULATIONAHA.111.034512