Abstract 12: S-Nitrosylation Invokes Functional Recovery from Experimental Stroke through the Hypoxia-inducible Factor-1 alpha/Vascular Endothelial Growth Factor Pathway
Background: In stroke patients, the stimulation of neurorepair mechanisms is necessary to reduce morbidity and disability. Our studies on brain and spinal cord trauma show that an exogenous treatment with the S-nitrosylating agent S-nitrosoglutathione (GSNO) stimulates neurorepair and aids functional recovery. Using a rat model of cerebral ischemia reperfusion (IR), we tested the hypothesis that GSNO invokes the neurorepair process and improves neurobehavioral functions through the angiogenic HIF-1α/VEGF pathway.
Methods: Stroke was induced by middle cerebral artery occlusion for 60 min followed by reperfusion in adult male rats. The injured animals were treated with vehicle (IR group, n=7), GSNO (0.25 mg/kg, GSNO group, n=7), and GSNO plus the HIF-1α inhibitor 2-mthoxyestradiol (0.25 mg/kg GSNO+5.0 mg/kg ME, GSNO+ME group, n=7). The groups were studied for 14 days to determine neurorepair mechanisms and functional recovery. Brain capillary endothelial cells were used to show that GSNO promotes angiogenesis and that GSNO-mediated induction of VEGF and the stimulation of angiogenesis are dependent on HIF-1α activity.
Results: GSNO treatment of IR enhanced the expression of HIF-1α, VEGF, and PECAM-1. This GSNO treatment also led to increased expression of neurorepair mediators including BDNF. Increased expression of VEGF/BDNF and the degree of tube formation (angiogenesis) by GSNO were reduced in an endothelial cell culture model after the inhibition of HIF-1α by ME. ME treatment of the GSNO group also blocked not only GSNO’s effect of reduced infarct volume (p<0.05) and enhanced expression of PECAM-1but also its improvement of motor and neurological functions (p<0.001).
Conclusions: GSNO shows therapeutic promise for stroke by stimulating the process of neurorepair and aiding functional recovery through the HIF-1α/VEGF/PECAM-1 dependent pathway.
Author Disclosures: M. Khan: None. T.S. Dhammu: None. F. Matsuda: None. I. Singh: None. A.K. Singh: None.
- © 2014 by American Heart Association, Inc.