Nitric oxide inhibits platelet adhesion to collagen through cGMP-dependent and independent mechanisms: The potential role for S-nitrosylation

Irwin, Catherine; Roberts, Wayne; Naseem, Khalid M.

doi:10.1080/09537100903159375

Cited by 14 publications

(20 citation statements)

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“…This treatment markedly enhanced arterial blood pressure, confirming that NO production was largely inhibited. As expected, L-NAME increased the adhesion of control platelets, confirming previous studies showing that NO inhibits platelet activation (Walter and Gambaryan, 2009;Irwin et al, 2009;Marcondes et al, 2006). However, the increased adhesion of non-activated platelet by LPS was reversed by L-NAME treatment.…”

Section: Discussionsupporting

confidence: 92%

Reactive oxygen and nitrogen species modulate the ex-vivo effects of LPS on platelet adhesion to fibrinogen

et al. 2011

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Section: Discussionsupporting

confidence: 92%

Reactive oxygen and nitrogen species modulate the ex-vivo effects of LPS on platelet adhesion to fibrinogen

et al. 2011

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“…[41][42][43][44] When incubated with NO donors, many proteins in platelets can be modified by S-nitrosylation. 40 However, whether the inhibitory effect of NO on platelet activation involves these sGC/cGMP-independent mechanisms is not known. While some studies suggested that sGCindependent mechanisms contribute to the inhibition of platelet activation by NO donors, 38,39,43,45 other investigators reported that NO donors fail to inhibit aggregation of the platelets isolated from whole body sGC deficiency mice lacking either ␣ 1 or ␤ 1 subunit of sGC 11,12,16 .…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacologic manipulations of the system may often mimic the inhibitory events triggered by higher concentrations of exogenously supplies NO. Although NO activates sGC and thus the cGMP pathway, it can also covalently modify other proteins or their metal cofactors, for example, through Snitrosylation (which converts thiol groups in proteins, into Snitrosothiols [SNOs]), [38][39][40] and nitration. [41][42][43][44] When incubated with NO donors, many proteins in platelets can be modified by S-nitrosylation.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Xiang

Dong

et al. 2011

Blood

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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 FeCl 3 -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. (Blood. 2011;118(13):3670-3679) IntroductionThe nitric oxide (NO)/cGMP signaling cascade is involved in diverse physiologic and pathophysiologic functions, such as smooth muscle relaxation, vasodilation, neurotransmission, immune responses, and inflammation. 1 NO is a short-lived gaseous molecule, synthesized by a family of enzymes known as nitric oxide synthase (NOS). There are 3 known NOS isoforms, neuronal NOS (nNOS, NOS1), inducible NOS (iNOS, NOS2), and endothelial NOS (eNOS, NOS3). Both eNOS and iNOS are expressed and functional in platelets. [2][3][4][5][6] The major effect of NO is mediated by its cytosolic receptor, soluble guanylyl cyclase (sGC). The roles of the NO/sGC/cGMP pathway in platelet activation have been investigated for Ͼ 3 decades. However, their functions in platelet activation remain controversial. There are 2 major controversies regarding the role of the NO-cGMP pathway in platelets: (1) whether the NO-cGMP pathway plays a stimulatory role, an inhibitory role, or both during platelet activation; and (2) whether the inhibitory effect of NO donors on platelet function is cGMPdependent or not. Early studies in the mid-1970's showed that during platelet activation by agonists, such as ADP and collagen, intracellular cGMP concentrations were enhanced significantly, 7,8 and that exogenous cGMP analogs enhanced platelet aggregation. 9 Therefore, a stimulatory role of cGMP in platelet activation was proposed. This view was soon abandoned because nitric oxide donors inhibited platelet activation, and dramatically increased intraplatelet cGMP concentrations. Since then, it has been generally accepted that cGMP plays an inhibitory...

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“…Exposure to NO results in a decreased number of free thiols on megakaryocyte and platelet surfaces 31 and S-nitrosylation of multiple platelet receptors including a IIb b 3 is observed following exposure to NO. 32 PDI undergoes S-nitrosylation following exposure to NO donors. 33 In contrast to S-nitrosylation at regulatory cysteines within platelet receptors such as a IIb b 3 , 34 S-nitrosylation of catalytic cysteines within PDI enables transfer of NO to other proteins and into cells.…”

Section: S-nitrosylation Of Thiol Isomerasesmentioning

confidence: 99%

Vascular thiol isomerases

Flaumenhaft

Furie

2016

Blood

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Thiol isomerases are multifunctional enzymes that influence protein structure via their oxidoreductase, isomerase, and chaperone activities. These enzymes localize at high concentrations in the endoplasmic reticulum of all eukaryotic cells where they serve an essential function in folding nascent proteins. However, thiol isomerases can escape endoplasmic retention and be secreted and localized on plasma membranes. Several thiol isomerases including protein disulfide isomerase, ERp57, and ERp5 are secreted by and localize to the membranes of platelets and endothelial cells. These vascular thiol isomerases are released following vessel injury and participate in thrombus formation. Although most of the activities of vascular thiol isomerases that contribute to thrombus formation are yet to be defined at the molecular level, allosteric disulfide bonds that are modified by thiol isomerases have been described in substrates such as αIIbβ3, αvβ3, GPIbα, tissue factor, and thrombospondin. Vascular thiol isomerases also act as redox sensors. They respond to the local redox environment and influence S-nitrosylation of surface proteins on platelets and endothelial cells. Despite our rudimentary understanding of the mechanisms by which thiol isomerases control vascular function, the clinical utility of targeting them in thrombotic disorders is already being explored in clinical trials.

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Nitric oxide inhibits platelet adhesion to collagen through cGMP-dependent and independent mechanisms: The potential role for S-nitrosylation

Cited by 14 publications

References 0 publications

Reactive oxygen and nitrogen species modulate the ex-vivo effects of LPS on platelet adhesion to fibrinogen

Reactive oxygen and nitrogen species modulate the ex-vivo effects of LPS on platelet adhesion to fibrinogen

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

Vascular thiol isomerases

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