A role for PLCγ2 in platelet activation by homocysteine

Leoncini, Giuliana; Bruzzese, Debora; Signorello, Maria Grazia

doi:10.1002/jcb.21123

Cited by 25 publications

(13 citation statements)

References 47 publications

(61 reference statements)

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“…The concentrations of Hcy and HTL were similar to those used in studies of other investigators [17,18]. The present study demonstrated that lipid peroxidation (measured using a colorimetric method dedicated to TBARS) of human plasma treated with the reduced form of Hcy and its thiolactone was distinctly increased compared with control (Fig.…”

Section: Discussionsupporting

confidence: 82%

Hydrogen sulfide decreases the plasma lipid peroxidation induced by homocysteine and its thiolactone

Olas

Kontek

2015

Mol Cell Biochem

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Hydrogen sulfide (H2S) has been investigated widely in recent years. H2S plays a variety of roles in different biological systems, including cardiovascular system. It is the final product of amino acids metabolism, which contains sulfur-cysteine and homocysteine (Hcy). In human plasma, there are several various forms of homocysteine: free Hcy, protein-bound Hcy (S-linked, and N-linked), and homocysteine thiolactone (HTL). Our previous works have shown that both Hcy in the reduced form and its thiolactone may modify fibrinolysis, coagulation process, and biological activity of blood platelets. Moreover, we have observed that HTL, like its precursor-Hcy stimulated the generation of superoxide anion radicals (O 2 (-•) ) in blood platelets. The aim of our study in vitro was to establish the influence of sodium hydrosulfide (NaHS, as a fast-releasing H2S donor; at tested concentrations: 10-1000 µM) on the plasma lipid peroxidation induced by the reduced Hcy (at final concentrations of 0.01-1 mM) and HTL (at final concentrations of 0.1-1 µM). Our results indicate that 10 and 100 µM NaHS decreased the lipid peroxidation in plasma treated with 1 mM Hcy or 1 µM HTL (when NaHS and Hcy/HTL were added to plasma together). The protective effect of 10 and 100 µM NaHS against the lipid peroxidation in plasma preincubated with 1 mM Hcy or 1 µM HTL was also observed. Considering the data presented in this study, we suggest that the lipid peroxidation (induced by different forms of homocysteine) may be reduced by hydrogen sulfide.

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Section: Discussionsupporting

confidence: 82%

Hydrogen sulfide decreases the plasma lipid peroxidation induced by homocysteine and its thiolactone

Olas

Kontek

2015

Mol Cell Biochem

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“…The concentrations of Hcys and HTL were similar to those used in studies of other investigators [37]. Here, we present evidences that not only the reduced form of Hcys, but also HTL (at lower concentrations than Hcys) induced platelet apoptosis in vitro (Figures 1-4).…”

Section: Discussionsupporting

confidence: 73%

Homocysteine and its thiolactone may promote apoptotic events in blood plateletsin vitro

2010

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The actions of homocysteine and its major metabolite, cyclic thioester, homocysteine thiolactone on endothelial cells, blood platelets, plasmatic fibrinogen and plasminogen--the important major components of haemostasis, regulating the flowing properties of blood--are complex and sometimes controversial. Homocysteine (Hcys) can promote apoptosis in endothelial cells, but the role of Hcys and its thiolactone in the apoptotic process in blood platelets is unknown. In order to study the appearance of apoptosis in platelets after treatment with the reduced form of Hcys or its thiolactone different markers were chosen: annexin V binding (phosphatidylserine exposure), platelet microparticle formation, mitochondrial membrane depolarization and αIIbβ3 expression in vitro. Apoptotic events and platelet activation were measured by a flow cytometer. In gel-filtered platelets treated with different concentrations of the reduced form of Hcys (25, 50 and 100 µM, 10 min) a significant increase of phosphatidylserine exposure (about 37% at the highest concentration, p < 0.001) and platelet microparticle formation were observed. Homocysteine caused also a dose-dependent depolarization of mitochondrial potential. The same apoptotic markers appeared in HTL-treated platelets (0.2 and 1 µM). Moreover, resveratrol (25 µM), a well known antioxidant, distinctly reduced the level of apoptotic markers. The obtained results indicate that Hcys and its thiolactone may promote in vitro apoptotic events in human gel-filtered platelets.

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“…***P < 0.001 and **P < 0.01 compared with 5.5 mM glucose; # P < 0.05 compared with 15 mM glucose; § § § P < 0.001 compared with baseline. let activation (17). As shown in Figure 7A, under both NG and HG conditions, the phosphorylation of PLCγ2 was significantly enhanced upon collagen-induced platelet aggregation.…”

Section: Figurementioning

confidence: 86%

Glucose and collagen regulate human platelet activity through aldose reductase induction of thromboxane

et al. 2011

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Diabetes mellitus is associated with platelet hyperactivity, which leads to increased morbidity and mortality from cardiovascular disease. This is coupled with enhanced levels of thromboxane (TX), an eicosanoid that facilitates platelet aggregation. Although intensely studied, the mechanism underlying the relationship among hyperglycemia, TX generation, and platelet hyperactivity remains unclear. We sought to identify key signaling components that connect high levels of glucose to TX generation and to examine their clinical relevance. In human platelets, aldose reductase synergistically modulated platelet response to both hyperglycemia and collagen exposure through a pathway involving ROS/PLCγ2/PKC/p38α MAPK. In clinical patients with platelet activation (deep vein thrombosis; saphenous vein graft occlusion after coronary bypass surgery), and particularly those with diabetes, urinary levels of a major enzymatic metabolite of TX (11-dehydro-TXB 2 [TX-M]) were substantially increased. Elevated TX-M persisted in diabetic patients taking low-dose aspirin (acetylsalicylic acid, ASA), suggesting that such patients may have underlying endothelial damage, collagen exposure, and thrombovascular disease. Thus, our study has identified multiple potential signaling targets for designing combination chemotherapies that could inhibit the synergistic activation of platelets by hyperglycemia and collagen exposure. IntroductionAccelerated atherosclerosis and microvascular disease contribute to the morbidity and mortality associated with diabetes mellitus (DM) (1-3). Vascular inflammation, endothelial dysfunction associated with hyperglycemia, impaired fibrinolysis, and increased coagulation factors as well as abnormal platelet function are typical for DM, contributing to the increased thrombotic events and development of arteriosclerosis (4). Altered platelet function in DM, including altered adhesion and aggregation, may contribute to the pathogenesis of DM vascular complications by promoting microthrombus formation, contributing to enhanced risk of small vessel occlusions and accelerated atherothrombotic diseases (5, 6). Patients with type 2 DM (T2DM) exhibit platelet hyperreactivity both in vitro and in vivo, coupled with biochemical evidence of persistently increased thromboxane-dependent (TX-dependent) platelet activation (7,8). Despite many important studies, the mechanism by which platelets transduce glucose levels into enhanced TX generation independently of endothelial and other blood cell-derived factors remains unclear. Similarly, optimal antiplatelet therapy for DM patients remains to be achieved.Aldose reductase (AR) is the first enzyme of the polyol pathway, and it represents a minor source of glucose utilization, accounting for less than 3% of glucose consumption during euglycemia.

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A role for PLCγ2 in platelet activation by homocysteine

Cited by 25 publications

References 47 publications

Hydrogen sulfide decreases the plasma lipid peroxidation induced by homocysteine and its thiolactone

Hydrogen sulfide decreases the plasma lipid peroxidation induced by homocysteine and its thiolactone

Homocysteine and its thiolactone may promote apoptotic events in blood plateletsin vitro

Glucose and collagen regulate human platelet activity through aldose reductase induction of thromboxane

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