Blockade of the natriuretic peptide receptor guanylyl cyclase-A inhibits NF-κB activation and alleviates myocardial ischemia/reperfusion injury
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
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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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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P-selectin expression in GC-A+/+ and GC-A–/– mice during myocardial isch...
P-selectin expression in GC-A+/+ and GC-A–/– mice during myocardial ischemia/reperfusion. (a–f) Immunolabeling of P-selectin in hearts from GC-A+/+ (a, c, and e) and GC-A–/– mice (b, d, and f); N, noninfarct tissue; I, infarct tissue. (a and b) Border zones between necrotic and nonischemic areas. (c and d) Perinecrotic areas. (e and f) High-power fields of perinecrotic areas. Levels of endothelial P-selectin expression in the border zones and in the centers of ischemic areas were lower in GC-A–/– hearts. (g) Western blot analysis showing P-selectin expression in LV of GC-A+/+ (lanes 1, 3, and 5) and GC-A–/– (lanes 2, 4, and 6) mice after 30 minutes of ischemia and 6 hours (lanes 3 and 4) or 2 days (lanes 5 and 6) of reperfusion. Lanes 1 and 2 show P-selectin expression without ischemia/reperfusion. (h) Semiquantitative analysis of P-selectin expression. P-selectin expression was significantly lower in GC-A–/– mice (filled bars) than in GC-A+/+ mice (open bars) after 6 hours or 2 days of reperfusion. *P < 0.01 vs. 6 hours of reperfusion in GC-A+/+ mice. #P < 0.01 vs. 2 days of reperfusion in GC-A+/+ mice.