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Published on: February 15, 2022
The Hemoglobin Homolog Cytoglobin in Smooth Muscle Inhibits Apoptosis and Regulates Vascular Remodeling
Frances L Jourd'heuil1, Haiyan Xu1, Timothy Reilly1
1From 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.).
Insights
Cytoglobin (CYGB) regulates vascular injury responses by inhibiting apoptosis in differentiated smooth muscle cells. Loss of CYGB promotes neointima formation and cell death after vascular injury.
Area of Science:
- Cardiovascular Biology
- Cellular Biology
- Molecular Medicine
Background:
- Hemoglobin and myoglobin roles in the cardiovascular system are known, but other globins, like cytoglobin (CYGB), are less understood.
- CYGB's specific function in vascular injury and smooth muscle cells requires further investigation.
Purpose of the Study:
- To investigate the expression and functional role of cytoglobin (CYGB) in vascular smooth muscle cells during vascular injury.
- To determine CYGB's impact on neointima formation and apoptosis following vascular injury.
Main Methods:
- Characterized CYGB expression in intact vessels and vascular smooth muscle (VSM) cells.
- Utilized rat balloon angioplasty and mouse carotid artery ligation models to assess CYGB's in vivo function.
- Employed shRNA delivery to inhibit CYGB reexpression and analyzed apoptosis markers (TUNEL, caspase-3).
Main Results:
- CYGB is highly expressed in differentiated medial VSM cells and veins, but lost upon VSM dedifferentiation.
- Inhibition of CYGB reexpression reduced neointima formation in a rat angioplasty model.
- Cygb knockout mice showed significantly less neointimal hyperplasia compared to wild-type littermates.
- Loss of CYGB sensitized VSM cells to apoptosis, which was linked to increased caspase-3 activation and reversed by antioxidant treatment or NOS2 inhibition.
Conclusions:
- CYGB is primarily expressed in differentiated medial VSM cells and plays a crucial role in regulating neointima formation after vascular injury.
- CYGB acts as an inhibitor of apoptosis in VSM cells following vascular injury, protecting against excessive cell loss.
- CYGB's protective effects are associated with antioxidant and nitric oxide synthase pathways.
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.
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