The hemoglobin homolog cytoglobin in smooth muscle inhibits apoptosis and regulates vascular remodeling

Frances L. Jourd'heuil, Haiyan Xu, Timothy Reilly, Keneta McKellar, Chaymae El Alaoui, Julia Steppich, Yong Feng Liu, Wen Zhao, Roman Ginnan, David Conti, Reynold Lopez-Soler, Arif Asif, Rebecca K. Keller, John J. Schwarz, Le Thi Thanh Thuy, Norifumi Kawada, Xiaochun Long, Harold A. Singer, David Jourd'heuil

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Objective - The role of hemoglobin and myoglobin in the cardiovascular system is well established, yet other globins in this context are poorly characterized. Here, we examined the expression and function of cytoglobin (CYGB) during vascular injury. Approach and Results - We characterized CYGB content in intact vessels and primary vascular smooth muscle (VSM) cells and used 2 different vascular injury models to examine the functional significance of CYGB in vivo. We found that CYGB was strongly expressed in medial arterial VSM and human veins. In vitro and in vivo studies indicated that CYGB was lost after VSM cell dedifferentiation. In the rat balloon angioplasty model, site-targeted delivery of adenovirus encoding shRNA specific for CYGB prevented its reexpression and decreased neointima formation. Similarly, 4 weeks after complete ligation of the left common carotid, Cygb knockout mice displayed little to no evidence of neointimal hyperplasia in contrast to their wild-type littermates. Mechanistic studies in the rat indicated that this was primarily associated with increased medial cell loss, terminal uridine nick-end labeling staining, and caspase-3 activation, all indicative of prolonged apoptosis. In vitro, CYGB could be reexpressed after VSM stimulation with cytokines and hypoxia and loss of CYGB sensitized human and rat aortic VSM cells to apoptosis. This was reversed after antioxidant treatment or NOS2 (nitric oxide synthase 2) inhibition. Conclusions - These results indicate that CYGB is expressed in vessels primarily in differentiated medial VSM cells where it regulates neointima formation and inhibits apoptosis after injury.

Original languageEnglish (US)
Pages (from-to)1944-1955
Number of pages12
JournalArteriosclerosis, thrombosis, and vascular biology
Volume37
Issue number10
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Keywords

  • Angioplasty
  • Apoptosis
  • Arteriovenous fistula
  • Myoglobin
  • Nitric oxide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Jourd'heuil, F. L., Xu, H., Reilly, T., McKellar, K., El Alaoui, C., Steppich, J., Liu, Y. F., Zhao, W., Ginnan, R., Conti, D., Lopez-Soler, R., Asif, A., Keller, R. K., Schwarz, J. J., Thuy, L. T. T., Kawada, N., Long, X., Singer, H. A., & Jourd'heuil, D. (2017). The hemoglobin homolog cytoglobin in smooth muscle inhibits apoptosis and regulates vascular remodeling. Arteriosclerosis, thrombosis, and vascular biology, 37(10), 1944-1955. https://doi.org/10.1161/ATVBAHA.117.309410