A stimulatory role for cGMP-dependent protein kinase in platelet activation.
It is currently accepted that cGMP-dependent protein kinase (PKG) inhibits platelet activation. Here, we show that PKG plays an important stimulatory role in platelet activation. Expression of recombinant PKG in a reconstituted cell model enhanced von Willebrand factor (vWF)-induced activation of the platelet integrin alpha(IIb)beta(3). PKG knockout mice showed impaired platelet responses to vWF or low doses of thrombin and prolonged bleeding time. Human platelet aggregation induced by vWF or low-dose thrombin was inhibited by PKG inhibitors but enhanced by cGMP. Furthermore, a cGMP-enhancing agent, sildenafil, promoted vWF- or thrombin-induced platelet aggregation. The cGMP-stimulated platelet responses are biphasic, consisting of an initial transient stimulatory response that promotes platelet aggregation and a subsequent inhibitory response that limits the size of thrombi.
Li
Zhenyu
Z
Department of Pharmacology, College of Medicine, University of Illinois, 835 South Wolcott Avenue, Chicago, IL 60612, USA.
Xi
Xiaodong
X
Gu
Minyi
M
Feil
Robert
R
Ye
Richard D
RD
Eigenthaler
Martin
M
Hofmann
Franz
F
Du
Xiaoping
X
D000818:Animals; D001792:Blood Platelets / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D006152:Cyclic GMP / Q000032:analysis; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D011687:Purines; D018080:Receptors, GABA-B; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D000068677:Sildenafil Citrate; D013450:Sulfones; D013917:Thrombin / Q000494:pharmacology / Q000502:physiology; D014841:von Willebrand Factor / Q000378:metabolism / Q000494:pharmacology
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019038:Platelet Glycoprotein GPIb-IX Complex; D011687:Purines; D018080:Receptors, GABA-B; D011994:Recombinant Proteins; D013450:Sulfones; D014841:von Willebrand Factor; D000068677:Sildenafil Citrate; D017869:Cyclic GMP-Dependent Protein Kinases; D013917:Thrombin; D006152:Cyclic GMP