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Arterioscler Thromb Vasc Biol. 2017 Oct;37(10):1944-1955. doi: 10.1161/ATVBAHA.117.309410. Epub 2017 Aug 10.

The Hemoglobin Homolog Cytoglobin in Smooth Muscle Inhibits Apoptosis and Regulates Vascular Remodeling.

Author information

1
From the Department of Molecular and Cellular Physiology (F.L.J., H.X., T.R., K.M., C.E.A., J.S., Y.F.L., W.Z., R.G., R.K.K., J.J.S., X.L., H.A.S., D.J.) and Surgery Transplantation (D.C., R.L.-S.), Albany Medical Center, NY; Seton Hall-Hackensack Meridian School of Medicine, Jersey Shore University Medical Center, Hackensack-Meridian Health, Neptune, NJ (A.A.); and Department of Hepatology, Graduate School of Medicine, Osaka City University, Japan (L.T.T.T., N.K.).
2
From the Department of Molecular and Cellular Physiology (F.L.J., H.X., T.R., K.M., C.E.A., J.S., Y.F.L., W.Z., R.G., R.K.K., J.J.S., X.L., H.A.S., D.J.) and Surgery Transplantation (D.C., R.L.-S.), Albany Medical Center, NY; Seton Hall-Hackensack Meridian School of Medicine, Jersey Shore University Medical Center, Hackensack-Meridian Health, Neptune, NJ (A.A.); and Department of Hepatology, Graduate School of Medicine, Osaka City University, Japan (L.T.T.T., N.K.). jourdhd@mail.amc.edu.

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.

KEYWORDS:

angioplasty; apoptosis; arteriovenous fistula; myoglobin; nitric oxide

Comment in

PMID:
28798140
PMCID:
PMC5620122
DOI:
10.1161/ATVBAHA.117.309410
[Indexed for MEDLINE]
Free PMC Article

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