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Biphasic roles for soluble guanylyl cyclase (sGC) in platelet activation
Journal article

Biphasic roles for soluble guanylyl cyclase (sGC) in platelet activation

  • Zhang, Guoying Division of Cardiovascular Medicine, Saha Cardiovascular Center, University of Kentucky, Lexington, KY;
  • Xiang, Binggang Division of Cardiovascular Medicine, Saha Cardiovascular Center, University of Kentucky, Lexington, KY;
  • Dong, Anping Division of Cardiovascular Medicine, Saha Cardiovascular Center, University of Kentucky, Lexington, KY;
  • Skoda, Radek C. Department of Biomedicine, Experimental Hematology, University Hospital Basel, Basel, Switzerland;
  • Daugherty, Alan Division of Cardiovascular Medicine, Saha Cardiovascular Center, University of Kentucky, Lexington, KY;
  • Smyth, Susan S. The Lexington VA Medical Center; and
  • Du, Xiaoping Department of Pharmacology, College of Medicine, University of Illinois, Chicago, IL
  • Li, Zhenyu Division of Cardiovascular Medicine, Saha Cardiovascular Center, University of Kentucky, Lexington, KY;
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Published in:
  • Blood. - American Society of Hematology. - 2011, vol. 118, no. 13, p. 3670-3679
Immunology
Cell Biology
Biochemistry
Hematology
English AbstractNitric oxide (NO) stimulates cGMP synthesis by activating its intracellular receptor, soluble guanylyl cyclase (sGC). It is a currently prevailing concept that No and cGMP inhibits platelet function. However, the data supporting the inhibitory role of NO/sGC/cGMP in platelets have been obtained either in vitro or using whole body gene deletion that affects vessel wall function. Here we have generated mice with sGC gene deleted only in megakaryocytes and platelets. Using the megakaryocyte- and platelet-specific sGC-deficient mice, we identify a stimulatory role of sGC in platelet activation and in thrombosis in vivo. Deletion of sGC in platelets abolished cGMP production induced by either NO donors or platelet agonists, caused a marked defect in aggregation and attenuated secretion in response to low doses of collagen or thrombin. Importantly, megakaryocyte- and platelet-specific sGC deficient mice showed prolonged tail-bleeding times and impaired FeCl3-induced carotid artery thrombosis in vivo. Interestingly, the inhibitory effect of the NO donor SNP on platelet activation was sGC-dependent only at micromolar concentrations, but sGC-independent at millimolar concentrations. Together, our data demonstrate important roles of sGC in stimulating platelet activation and in vivo thrombosis and hemostasis, and sGC-dependent and -independent inhibition of platelets by NO donors.
Language
  • English
Open access status
green
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Persistent URL
https://sonar.ch/global/documents/238182
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