Blockade of the natriuretic peptide receptor guanylyl cyclase-A inhibits NF-κB activation and alleviates myocardial ischemia/reperfusion injury
Takehiko Izumi, … , Seibu Mochizuki, Kazuwa Nakao
Takehiko Izumi, … , Seibu Mochizuki, Kazuwa Nakao
Published July 15, 2001
Citation Information: J Clin Invest. 2001;108(2):203-213. https://doi.org/10.1172/JCI12088.
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Article

Blockade of the natriuretic peptide receptor guanylyl cyclase-A inhibits NF-κB 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-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.

Authors

Takehiko Izumi, Yoshihiko Saito, Ichiro Kishimoto, Masaki Harada, Koichiro Kuwahara, Ichiro Hamanaka, Nobuki Takahashi, Rika Kawakami, Yuhao Li, Genzo Takemura, Hisayoshi Fujiwara, David L. Garbers, Seibu Mochizuki, Kazuwa Nakao

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Figure 1

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Evaluation of infarct size and AAR in hearts from GC-A+/+ and GC-A–/– mi...
Evaluation of infarct size and AAR in hearts from GC-A+/+ and GC-A–/– mice subjected to 30 minutes of ischemia and 2 days of reperfusion. (a) Representative photographs of midventricular myocardial tissue from GC-A+/+ and GC-A–/– mice. Note that the infarct area (white color) in the GC-A–/– mouse is smaller than that in the GC-A+/+ mouse. (b) Schema of photographs of a. Infarct area is expressed as light blue, AAR is red, and nonischemic area is blue. (c) There was no significant difference in myocardial AAR/LV ratios in GC-A+/+ and GC-A–/– mice. (d) Myocardial infarct/AAR ratios in GC-A–/– mice were significantly smaller than in GC-A+/+ mice. (e) Infarct/LV ratios in GC-A–/– mice were significantly smaller than in GC-A+/+ mice. *P < 0.05 vs. GC-A+/+ mice.