Abstract 16379: Protein Tyrosine Phosphatases as Novel Therapeutic Targets Against Ischemic Damage to the Heart
Background: Recent examples showed that disruption of protein tyrosine phosphate (PTP) function as an underlying cause of human diseases and recent studies had reported that PTPs inhibition can improve peripheral endothelial dysfunction in animal models of chronic heart failure. However, the role of PTPs in acute cardiac ischemia is unknown and no prior literature can be found.
Methods: We used biotinylated a-bromobenzyl phosphonate probe and modified cysteinyl-labeling assay for reversible oxidation, with intention to demonstrate that hypoxia-driven reduction of the active-site Cys residue is the key to activate endogenous PTPs in H9c2 cells. For in vivo study, we used acute myocardial infarction (MI) mouse model and measured the PTP activity 2 hours post left anterior desending coronary artery ligation.
Results: We showed that phosphotyrosine (pTyr) signaling was perturbed concomitantly with increased activity of PTPs in hypoxic H9c2 cells and in early hours in MI mouse heart. We also demonstrated that hypoxia-driven reduction of the active-site Cys residue is the key to activate endogenous PTPs, in which resulted in diminished pTyr signaling associated with a loss of F-actin cytoskeletal integrity. For therapy, we used nitric oxide donors s-nitrosoglutathione (GSNO) and demonstarted attenuation of pTyr signaling perturbation and cytoskeletal disruption in hypoxic H9c2 cells. In addition, ischemia-induced cardiac injury in mice was markedly attenuated by GSNO treatment through either intraperitoneal injection (GSNO, 5 mg/kg 10 minutes before cardiac infarction surgery) or intracardiac injection (GSNO, 1 mg/kg immediately injected on 5 position near the infraction sites), with a significant rebound of pTyr signaling and a decrease in cardiac enzyme including CPK and LDH.
Conclusion: Together our data confirms a protective role of NO to the ischemic heart via s-nitrosylation and inactivation of PTPs. This study also revealing the potential for PTPs to represent a new class of therapeutic target in early stage of cardiac ischemia.
- © 2013 by American Heart Association, Inc.