title: Blockade of the natriuretic peptide receptor guanylyl cyclase-A inhibits NF-kappaB activation and alleviates myocardial ischemia/reperfusion injury.
abstract: Acute myocardial infarction (AMI) remains the leading cause of death in developed countries. Although reperfusion of coronary arteries reduces mortality, it is associated with tissue injury. Endothelial P-selectin-mediated infiltration of neutrophils plays a key role in reperfusion injury. However, the mechanism of the P-selectin induction is not known. Here we show that infarct size after ischemia/reperfusion was significantly smaller in mice lacking guanylyl cyclase-A (GC-A), a natriuretic peptide receptor. The decrease was accompanied by decreases in neutrophil infiltration in coronary endothelial P-selectin expression. Pretreatment with HS-142-1, a GC-A antagonist, also decreased infarct size and P-selectin induction in wild-type mice. In cultured endothelial cells, activation of GC-A augmented H2O2-induced P-selectin expression. Furthermore, ischemia/reperfusion-induced activation of NF-kappaB, a transcription factor that is known to promote P-selectin expression, is suppressed in GC-A-deficient mice. These results suggest that inhibition of GC-A alleviates ischemia/reperfusion injury through suppression of NF-kappaB-mediated P-selectin induction. This novel, GC-A-mediated mechanism of ischemia/reperfusion injury may provide the basis for applying GC-A blockade in the clinical treatment of reperfusion injury.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Izumi
authors.forename: Y
authors.initials: Y
authors.lastname: Saito
authors.forename: I
authors.initials: I
authors.lastname: Kishimoto
authors.forename: M
authors.initials: M
authors.lastname: Harada
authors.forename: K
authors.initials: K
authors.lastname: Kuwahara
authors.forename: I
authors.initials: I
authors.lastname: Hamanaka
authors.forename: N
authors.initials: N
authors.lastname: Takahashi
authors.forename: R
authors.initials: R
authors.lastname: Kawakami
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: G
authors.initials: G
authors.lastname: Takemura
authors.forename: H
authors.initials: H
authors.lastname: Fujiwara
authors.forename: D L
authors.initials: DL
authors.lastname: Garbers
authors.forename: S
authors.initials: S
authors.lastname: Mochizuki
authors.forename: K
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000032:analysis; D001666:Binding Sites, Antibody; D015153:Blotting, Western; D005070:Evans Blue; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors* / Q000172:deficiency; D006352:Heart Ventricles; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020097:Natriuretic Peptide, Brain; D009504:Neutrophils / Q000276:immunology; D019007:P-Selectin / Q000096:biosynthesis; D009195:Peroxidase / Q000032:analysis; D011134:Polysaccharides / Q000494:pharmacology; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors* / Q000172:deficiency; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation
chemical_list: C072551:HS 142-1; D016328:NF-kappa B; D019007:P-Selectin; D011134:Polysaccharides; D020097:Natriuretic Peptide, Brain; D005070:Evans Blue; D009320:Atrial Natriuretic Factor; D009195:Peroxidase; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A