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

The Journal of Clinical Investigation
T IzumiK Nakao

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 provi...Continue Reading

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Citations

Mar 7, 2003·Proceedings of the National Academy of Sciences of the United States of America·Kenichi YamaharaKazuwa Nakao
Feb 21, 2002·The Journal of Clinical Investigation·Masashi SuzukiHaruaki Nakaya
Oct 26, 2005·Circulation Journal : Official Journal of the Japanese Circulation Society·Keiji TanimotoKazuwa Nakao
Apr 21, 2007·Journal of Zhejiang University. Science. B·Xi-ping ZhangJie Zhang
Feb 8, 2008·Journal of Zhejiang University. Science. B·Xi-ping ZhangHan-qin Chen
Jan 18, 2008·Journal of the American Society of Nephrology : JASN·Heng LinRuey-Bing Yang
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Jan 24, 2003·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Rita CariniEmanuele Albano
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Feb 8, 2003·Hypertension·Colleen J Thomas, Robyn L Woods
Nov 12, 2002·Arteriosclerosis, Thrombosis, and Vascular Biology·El Mostafa MtairagJean-Baptiste Michel
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Methods Mentioned

BETA
protein assay
electrophoretic mobility shift assay
Assay
flow cytometry

Software Mentioned

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