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.
View: Text | PDF
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

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
PMN infiltration in GC-A+/+ and GC-A–/– mice subjected to myocardial isc...
PMN infiltration in GC-A+/+ and GC-A–/– mice subjected to myocardial ischemia/reperfusion. (a–d) H&E staining of myocardial tissue from GC-A+/+ and GC-A–/– mice obtained after 30 minutes of ischemia and 2 days of reperfusion. (a and c) Perinecrotic area of a GC-A+/+ mouse at magnification of ×100 and ×400, respectively. (b and d) Perinecrotic area of a GC-A–/– mouse at magnifications of ×100 and ×400, respectively. Note that significant numbers of PMNs accumulated in perinecrotic areas of GC-A+/+ mice, while a fewer PMNs infiltrated the GC-A–/– heart. (e) Average numbers of infiltrating PMNs per ×400 field in the myocardium subjected to 30 minutes of ischemia and either 6 hours or 2 days of reperfusion. After both 6 hours or 2 days of reperfusion, PMN numbers were significantly lower in GC-A–/– mice (filled bars) than in time-matched GC-A+/+ controls (open bars). *P < 0.01 vs. 6 hours of reperfusion in GC-A+/+ mice. #P < 0.01 vs. 2 days of reperfusion in GC-A+/+ mice. (f) Myocardial MPO activity in infarct and noninfarct cardiac tissue samples obtained from GC-A+/+ (open bars) and GC-A–/– mice (filled bars) after 30 minutes of ischemia and 6 hours or 2 days of reperfusion. MPO activity is expressed as U/100 mg wet tissue weight, which was decreased significantly in the infarct areas of GC-A–/– mice. *P < 0.05 vs. 6 hours of reperfusion in GC-A+/+ mice. #P < 0.01 vs. 2 days of reperfusion in GC-A+/+ mice.