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Biomaterials. 2013 Nov;34(33):8086-96. doi: 10.1016/j.biomaterials.2013.07.041. Epub 2013 Jul 29.

The mediation of platelet quiescence by NO-releasing polymers via cGMP-induced serine 239 phosphorylation of vasodilator-stimulated phosphoprotein.

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Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.


Nitric oxide (NO) releasing (NORel) materials have been shown to create localized increases in NO concentration by the release of NO from a diazeniumdiolate-containing or S-nitrosothiol-containing polymer coating and the improvement of extracorporeal circulation (ECC) hemocompatibility. However, the mechanism and, in particular, the platelet upregulation of the NO/cGMP signaling protein, vasodilator-stimulated phosphoprotein phosphorylated at serine 239 (P-VASP (ser 239)), for the improved ECC hemocompatibility via NO release still needs elucidation. In this work, two NORel polymeric coatings were evaluated in a 4 h rabbit thrombogenicity model and the anti-thrombotic mechanism investigated for rabbit platelet P-VASP upregulation. Polymer films containing 25 wt% diazeniumdiolated dibutylhexanediamine (DBHD) or 5 wt% S-nitroso-N-acetylpenicillamine (SNAP) coated on the inner walls of ECC circuits yielded significantly reduced ECC thrombus formation and maintained normal platelet aggregation compared to polymer controls after 4 h of blood exposure. Platelet P-VASP (ser 239), a useful tool to monitor NO/cGMP signaling, was upregulated after 4 h on ECC and markedly increased after ex vivo sodium nitroprusside (SNP) stimulation. Interestingly, in the rabbit platelet, NO did not upregulate the cAMP P-VASP phosphoprotein P-VASP (ser 157) as previously shown in human platelets. These results suggest that NORel polymers preserve rabbit platelet quiescence by sustaining a level of cGMP signaling as monitored by P-VASP (ser 239) upregulation. The upregulation of this NO-mediated platelet signaling mechanism in this rabbit thrombogenicity model indicates the potential for improved thromboresistance of any NORel-coated medical device.


DBHD; Extracorporeal circulation (ECC); Hemocompatibility; NO releasing; NORel; Nitric oxide (NO); P-VASP (ser 157); P-VASP (ser 239); Platelets; RSNO; S-nitrosothiol; SNP; Vasodilator-stimulated phosphoprotein (VASP); cGKI; cGMP; cGMP-dependent protein kinase types I β subunit; dibutylhexanediamine; sGC; serine 157 phosphorylation of VASP; serine 239 phosphorylation of VASP; sodium nitroprusside; soluble guanylate cyclase

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