title: Biphasic roles for soluble guanylyl cyclase (sGC) in platelet activation.
abstract: Nitric 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.
authors.affiliation: Division of Cardiovascular Medicine, Saha Cardiovascular Center, University of Kentucky, Lexington, KY, USA.
authors.forename: Guoying
authors.initials: G
authors.lastname: Zhang
authors.forename: Binggang
authors.initials: B
authors.lastname: Xiang
authors.forename: Anping
authors.initials: A
authors.lastname: Dong
authors.forename: Radek C
authors.initials: RC
authors.lastname: Skoda
authors.forename: Alan
authors.initials: A
authors.lastname: Daugherty
authors.forename: Susan S
authors.initials: SS
authors.lastname: Smyth
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Du
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D015539:Platelet Activation / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000071756:Soluble Guanylyl Cyclase
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP; D002118:Calcium