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: T Izumi, Y Saito, I Kishimoto, M Harada, K Kuwahara, I Hamanaka, N Takahashi, R Kawakami, Y Li, G Takemura, H Fujiwara, D L Garbers, S Mochizuki, K Nakao
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 108 Issue 2 Pg. 203-13 (Jul 2001) ISSN: 0021-9738 [Print] United States
• PMID: 11457873 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HS 142-1
• NF-kappa B
• P-Selectin
• Polysaccharides
• Natriuretic Peptide, Brain
• Evans Blue
• Atrial Natriuretic Factor
• Peroxidase
• Guanylate Cyclase
• Receptors, Atrial Natriuretic Factor
• atrial natriuretic factor receptor A

Topics

• Animals
• Atrial Natriuretic Factor (analysis)
• Binding Sites, Antibody
• Blotting, Western
• Evans Blue
• Guanylate Cyclase (antagonists & inhibitors, deficiency)
• Heart Ventricles
• Mice
• Mice, Inbred C57BL
• Myocardial Ischemia (pathology, prevention & control)
• Myocardial Reperfusion Injury (pathology, prevention & control)
• Myocardium (immunology, metabolism, pathology)
• NF-kappa B (analysis, antagonists & inhibitors, metabolism)
• Natriuretic Peptide, Brain
• Neutrophils (immunology)
• P-Selectin (biosynthesis)
• Peroxidase (analysis)
• Polysaccharides (pharmacology)
• Receptors, Atrial Natriuretic Factor (antagonists & inhibitors, deficiency)
• Signal Transduction (drug effects)
• Time Factors
• Up-Regulation