title: Nogo-A knockdown inhibits hypoxia/reoxygenation-induced activation of mitochondrial-dependent apoptosis in cardiomyocytes.
abstract: Programmed cell death of cardiomyocytes following myocardial ischemia increases biomechanical stress on the remaining myocardium, leading to myocardial dysfunction that may result in congestive heart failure or sudden death. Nogo-A is well characterized as a potent inhibitor of axonal regeneration and plasticity in the central nervous system, however, the role of Nogo-A in non-nervous tissues is essentially unknown. In this study, Nogo-A expression was shown to be significantly increased in cardiac tissue from patients with dilated cardiomyopathy and from patients who have experienced an ischemic event. Nogo-A expression was clearly associated with cardiomyocytes in culture and was localized predominantly in the endoplasmic reticulum. In agreement with the findings from human tissue, Nogo-A expression was significantly increased in cultured neonatal rat cardiomyocytes subjected to hypoxia/reoxygenation. Knockdown of Nogo-A in cardiomyocytes markedly attenuated hypoxia/reoxygenation-induced apoptosis, as indicated by the significant reduction of DNA fragmentation, phosphatidylserine translocation, and caspase-3 cleavage, by a mechanism involving the preservation of mitochondrial membrane potential, the inhibition of ROS accumulation, and the improvement of intracellular calcium regulation. Together, these data demonstrate that knockdown of Nogo-A may serve as a novel therapeutic strategy to prevent the loss of cardiomyocytes following ischemic/hypoxic injury.
authors.affiliation: Department of Cell and Molecular Physiology, Loyola University Medical Center, Maywood, IL, USA. jsarkey@lumc.edu
authors.forename: J P
authors.initials: JP
authors.lastname: Sarkey
authors.forename: M
authors.initials: M
authors.lastname: Chu
authors.forename: M
authors.initials: M
authors.lastname: McShane
authors.forename: E
authors.initials: E
authors.lastname: Bovo
authors.forename: Y
authors.initials: Y
authors.lastname: Ait Mou
authors.forename: A V
authors.initials: AV
authors.lastname: Zima
authors.forename: P P
authors.initials: PP
authors.lastname: de Tombe
authors.forename: G L
authors.initials: GL
authors.lastname: Kartje
authors.forename: J L
authors.initials: JL
authors.lastname: Martin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D009185:Myelin Proteins / Q000235:genetics*; D017202:Myocardial Ischemia / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism*; D000070798:Nogo Proteins; D010718:Phosphatidylserines / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D009185:Myelin Proteins; D000070798:Nogo Proteins; D010718:Phosphatidylserines; C000603199:RTN4 protein, human; D017382:Reactive Oxygen Species; C000603197:Rtn4 protein, rat; D045304:Cytochromes c; D053148:Caspase 3; D002118:Calcium