Blockade of the natriuretic peptide receptor guanylyl cyclase-A inhibits NF-κB activation and alleviates myocardial ischemia/reperfusion injury

• Published in: The Journal of clinical investigation 2001-07, Vol.108 (2), p.203-213
• Main Authors: Izumi, Takehiko, Saito, Yoshihiko, Kishimoto, Ichiro, Harada, Masaki, Kuwahara, Koichiro, Hamanaka, Ichiro, Takahashi, Nobuki, Kawakami, Rika, Li, Yuhao, Takemura, Genzo, Fujiwara, Hisayoshi, Garbers, David L., Mochizuki, Seibu, Nakao, Kazuwa
• Format: Article
• Language: English
• ISSN: 0021-9738
• DOI: 10.1172/JCI12088

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 H 2 O 2 -induced P-selectin expression. Furthermore, ischemia/reperfusion–induced activation of NF-κB, 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-κB–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.