Cyclic GMP-independent mechanisms contribute to the inhibition of platelet adhesion by nitric oxide donor: A role for α-actinin nitration

Marcondes, Sisi; Cardoso, Marcia Hlena Miranda; Morganti, Rafael P.; Thomazzi, Sara Maria; Lilla, Sérgio; Murad, Ferid; Nucci, Gilberto De; Antunes, Edson

doi:10.1073/pnas.0509397103

Cited by 84 publications

(63 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Nitric oxide is a simple inorganic radical exhibiting diverse physiological functions, including the regulation of neurotransmission and vascular tone (12,15). Peroxynitrite, a biological toxin, produced in vivo by the nearly diffusion-controlled reaction of nitrogen monoxide with superoxide, can nitrate and oxidize various biomolecules, such as thiols, lipids, carbohydrates, and nucleic acids (16).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Antioxidative activity of Ginkgo, Echinacea, and Ginseng tinctures

et al. 2007

View full text Add to dashboard Cite

Summary. The aim of this study was to determine the amount of phenol compounds in tinctures prepared from Ginkgo leaves, Echinacea plant, and Ginseng roots and toMedicina (Kaunas) 2007; 43(4) Correspondence to J. Bernatonienė, Department of Drugs Technology and Social Pharmacy, Kaunas University of Medicine, A. Mickevičiaus 9, 44307 Kaunas, Lithuania. E-mail: jurgabernatoniene@yahoo.com IntroductionThe cause of coronary heart diseases, cancers, and aging processes is oxidative stress that is caused by free radicals (1, 2). One of the ways to prevent the aforementioned pathologies is application of antioxidants. Antioxidants are compounds that protect cells against the damaging effects of reactive oxygen species (3). Experimental studies were performed on three plants that have antioxidative properties -Ginkgo biloba, Panax ginseng, and Echinacea purpurea (4). Ginkgo biloba preparations are used in the treatment of Parkinson's and Alzheimer's diseases caused by oxidative stress. Studies have shown that oxidative stress is related to cancer, aging, atherosclerosis, ischemic injury, inflammation, and neurodegenerative diseases (5). Studies by Bulgarian researchers showed that Panax ginseng preparations had antioxidant activity and were used for chemotherapy prophylaxis (6).

show abstract

Section: Resultsmentioning

confidence: 99%

“…Peroxynitrite solution was prepared according to methods indicated in literature (12). Aliquots of 0.6 M H 2 O 2 (in 0.5 M HClO 4 ) and 0.5 M NaNO 2 (in water) (10 mL each) were pre-cooled to -2°C and mixed rapidly.…”

Section: Reagents and Samplesmentioning

confidence: 99%

Antioxidative activity of Ginkgo, Echinacea, and Ginseng tinctures

et al. 2007

View full text Add to dashboard Cite

show abstract

“…It is well accepted that NO-mediated actions are due to activation of the soluble guanylate cyclase (sGC) leading to an increase of cGMP, but cGMP-independent mechanisms have been suggested as potential signaling pathways modulating the NO-induced responses (Marcondes et al, 2006). NO can act by directly modifying cysteine residues in target proteins (Stamler et al, 2001;Hess et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Hippocampal Neuronal Nitric Oxide Synthase Mediates the Stress-Related Depressive Behaviors of Glucocorticoids by Downregulating Glucocorticoid Receptor

Zhou¹,

Zhu²,

Chen³

et al. 2011

J. Neurosci.

131

130

View full text Add to dashboard Cite

The molecular mechanisms underlying the behavioral effects of glucocorticoids are poorly understood. We report here that hippocampal neuronal nitric oxide synthase (nNOS) is a crucial mediator. Chronic mild stress and glucocorticoids exposures caused hippocampal nNOS overexpression via activating mineralocorticoid receptor. In turn, hippocampal nNOS-derived nitric oxide (NO) significantly downregulated local glucocorticoid receptor expression through both soluble guanylate cyclase (sGC)/cGMP and peroxynitrite (ONOO Ϫ )/extracellular signal-regulated kinase signal pathways, and therefore elevated hypothalamic corticotrophin-releasing factor, a peptide that governs the hypothalamic-pituitary-adrenal axis. More importantly, nNOS deletion or intrahippocampal nNOS inhibition and NO-cGMP signaling blockade (using NO scavenger or sGC inhibitor) prevented the corticosterone-induced behavioral modifications, suggesting that hippocampal nNOS is necessary for the role of glucocorticoids in mediating depressive behaviors. In addition, directly delivering ONOO Ϫ donor into hippocampus caused depressive-like behaviors. Our findings reveal a role of hippocampal nNOS in regulating the behavioral effects of glucocorticoids.

show abstract

“…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. 40 However, whether the inhibitory effect of NO on platelet activation involves these sGC/cGMP-independent mechanisms is not known.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Xiang

Dong

et al. 2011

Blood

View full text Add to dashboard Cite

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...

show abstract

Cyclic GMP-independent mechanisms contribute to the inhibition of platelet adhesion by nitric oxide donor: A role for α-actinin nitration

Cited by 84 publications

References 48 publications

Antioxidative activity of Ginkgo, Echinacea, and Ginseng tinctures

Antioxidative activity of Ginkgo, Echinacea, and Ginseng tinctures

Hippocampal Neuronal Nitric Oxide Synthase Mediates the Stress-Related Depressive Behaviors of Glucocorticoids by Downregulating Glucocorticoid Receptor

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

Contact Info

Product

Resources

About