337 - Cytoglobin Prevents Redox-Dependent Smooth Muscle Cell Apoptosis During Vascular Injury

Abstract

Objective Cytoglobin (CYGB) is a hemoglobin with an affinity for molecular oxygen comparable to myoglobin. Cytoglobin is expressed in vascular smooth muscle cells and regulates cell survival during conditions associated with oxidative stress through unknown mechanisms. Methods and Results In this study, we show that CYGB is the primary globin expressed in medial smooth muscle cells, in human and rodent large arteries. The expression of CYGB is acutely downregulated in mouse and rat models of vascular injury and re-expressed in more chronic conditions when neointimal hyperplasia is maximal. Decrease in CYGB levels through adenoviral delivery of shRNA targeting Cygb resulted in reduced neointimal hyperplasia, which could not be attributed to an inhibition of cell proliferation but rather was due to an increase in smooth muscle cell apoptosis. Mechanistic studies in situ and in vitro revealed that the observed increase in smooth muscle cell apoptosis was mediated through an increase in caspase-8 and -3-activation and that dual inhibition of CYGB and oxidative stress resulted in a reversal of the vascular phenotype. Conclusion The present study indicates a novel function for globins in the vasculature independent of their known oxygen storage/transport roles, which instead is associated with the redox sensitive repression of caspase-8 and -3 dependent apoptosis.