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The Biochemical Journal Mar 2015Rho GTPases are critical for platelet function. Although the roles of RhoA, Rac and Cdc42 are characterized, platelets express other Rho GTPases, whose activities are... (Review)
Review
Rho GTPases are critical for platelet function. Although the roles of RhoA, Rac and Cdc42 are characterized, platelets express other Rho GTPases, whose activities are less well understood. This review summarizes our understanding of the roles of platelet Rho GTPases and focuses particularly on the functions of Rif and RhoG. In human platelets, Rif interacts with cytoskeleton regulators including formins mDia1 and mDia3, whereas RhoG binds SNARE-complex proteins and cytoskeletal regulators ELMO and DOCK1. Knockout mouse studies suggest that Rif plays no critical functions in platelets, likely due to functional overlap with other Rho GTPases. In contrast, RhoG is essential for normal granule secretion downstream of the collagen receptor GPVI. The central defect in RhoG-/- platelets is reduced dense granule secretion, which impedes integrin activation and aggregation and limits platelet recruitment to growing thrombi under shear, translating into reduced thrombus formation in vivo. Potential avenues for future work on Rho GTPases in platelets are also highlighted, including identification of the key regulator for platelet filopodia formation and investigation of the role of the many Rho GTPase regulators in platelet function in both health and disease.
Topics: Animals; Blood Platelets; Humans; Platelet Activation; Platelet Aggregation; Signal Transduction; rho GTP-Binding Proteins
PubMed: 25748676
DOI: 10.1042/BJ20141404 -
Redox Biology May 2020Previously we have shown that wheat germ agglutinin (WGA) and, with minor potency, Phaseolus vulgaris agglutinin (PHA), but not lens culinarian agglutinin (LCA), induce...
Previously we have shown that wheat germ agglutinin (WGA) and, with minor potency, Phaseolus vulgaris agglutinin (PHA), but not lens culinarian agglutinin (LCA), induce platelet aggregation, through the PLCƴ2 activation by the concerted action of src/syk and PI3K/BTK pathways. In this study, we have investigated platelet oxidative stress induced by lectins. Several parameters indicative of oxidative stress, such as reactive oxygen species (ROS), superoxide anion, lipid peroxidation and the efficiency of the aerobic metabolism, have been measured. It was found that ROS, superoxide anion formation and lipid peroxidation are significantly increased upon platelet treatment with WGA and PHA while LCA is ineffective. WGA is always more effective than PHA in all experimental conditions tested. In addition, the involvement of NADPH oxidase 1, syk and PI3K in oxidative stress induced by WGA and PHA has been shown. Concerning the lectins effect on aerobic metabolism, WGA and PHA, but not LCA, act as uncoupling agents, determining an increase of oxygen consumption and a decrease of ATP synthesis, with a consequent decrease of P/O value. These results are confirmed by the impairment of platelets proton gradient formation, evaluated by membrane potential, in platelets treated with WGA and PHA. In conclusion lectins, especially WGA, induce oxidative stress in platelets and decrease energy availability through modifications of membrane structure leading to the inefficiency of the aerobic machinery that steers platelets toward death as suggested by the decreased metabolic activity of platelets and the increased lactic dehydrogenase release.
Topics: Blood Platelets; Humans; Lectins; Oxidative Stress; Platelet Aggregation; Wheat Germ Agglutinins
PubMed: 32063518
DOI: 10.1016/j.redox.2020.101456 -
International Journal of Molecular... Nov 2021Cardiovascular disease is strongly influenced by platelet activation. Platelet activation and thrombus formation at atherosclerotic plaque rupture sites is a dynamic... (Review)
Review
Cardiovascular disease is strongly influenced by platelet activation. Platelet activation and thrombus formation at atherosclerotic plaque rupture sites is a dynamic process regulated by different signaling networks. Therefore, there are now focused efforts to search for novel bioactive compounds which target receptors and pathways in the platelet activation process while preserving normal hemostatic function. The antiplatelet activity of numerous fruits and vegetables and their multiple mechanisms of action have recently been highlighted. In this review, we review the antiplatelet actions of bioactive compounds via key pathways (protein disulfide isomerase, mitogen-activated protein kinases, mitochondrial function, cyclic adenosine monophosphate, Akt, and shear stress-induced platelet aggregation) with no effects on bleeding time. Therefore, targeting these pathways might lead to the development of effective antiplatelet strategies that do not increase the risk of bleeding.
Topics: Animals; Blood Platelets; Hemorrhage; Hemostasis; Humans; Phytochemicals; Plaque, Atherosclerotic; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Thrombosis
PubMed: 34830261
DOI: 10.3390/ijms222212380 -
Ginekologia Polska 2022The aim of the study was to evaluate platelet (PLT) concentration, mean platelet volume (MPV), PLT aggregation and its velocity in pregnancy complicated with fetal...
OBJECTIVES
The aim of the study was to evaluate platelet (PLT) concentration, mean platelet volume (MPV), PLT aggregation and its velocity in pregnancy complicated with fetal growth restriction (FGR) and to analyze the PLT aggregation according to the gestational age and Doppler velocimetry.
MATERIAL AND METHODS
The study group included 29 pregnant women diagnosed with FGR. The control group-consisted of 27 females in uncomplicated pregnancy. Then both groups were divided according to the gestational week (< and ≥ 36 weeks) and Doppler velocimetry results. The adenosine diphosphate (ADP) induced PLT aggregation was performed with the help of the electrical impedance.
RESULTS
There was a significant positive correlation between gestational age and PLT aggregation and between gestational age and velocity of PLT aggregation in FGR. Patients with FGR ≥ 36 weeks of gestation had 73% higher PLT aggregation than control group. Within the FGR group, the PLT aggregation was 135% higher in pregnancies ≥ 36 weeks as compared to < 36 weeks of gestation. In FGR pregnancies ≥ 36 weeks with impaired flow in both uterine arteries (UtA), 2.3-fold higher PLT aggregation was found as compared to FGR patients with normal flow or abnormal flow in one UtA.
CONCLUSIONS
The increased PLT aggregation in FGR is related to gestational week and occurs in pregnancies ≥ 36 weeks of gestation. The PLT hyperaggregability in growth-restricted pregnancies is associated with abnormal Doppler velocimetry in both UtA, comparing to patients with altered blood flow in one UtA or normal pulsatility index in both UtA, suggesting the PLT activation due to impaired uteroplacental circulation.
Topics: Pregnancy; Female; Humans; Fetal Growth Retardation; Platelet Aggregation; Ultrasonography, Prenatal; Pregnancy Trimester, Third; Uterine Artery; Gestational Age
PubMed: 35325455
DOI: 10.5603/GP.a2022.0006 -
International Journal of Molecular... Mar 2021Lipids play an essential role in platelet functions. It is known that polyunsaturated fatty acids play a role in increasing platelet reactivity and that the... (Review)
Review
Lipids play an essential role in platelet functions. It is known that polyunsaturated fatty acids play a role in increasing platelet reactivity and that the prothrombotic phenotype plays a crucial role in the occurrence of major adverse cardiovascular events. The ongoing increase in cardiovascular diseases' incidence emphasizes the importance of research linking lipids and platelet function. In particular, the rebound phenomenon that accompanies discontinuation of clopidogrel in patients receiving dual antiplatelet therapy has been associated with changes in the lipid profile. Our many years of research underline the importance of reduced HDL values for the risk of such a rebound effect and the occurrence of thromboembolic events. Lipids are otherwise a heterogeneous group of molecules, and their signaling molecules are not deposited but formed "on-demand" in the cell. On the other hand, exosomes transmit lipid signals between cells, and the profile of such changes can be monitored by lipidomics. Changes in the lipid profile are organ-specific and may indicate new drug action targets.
Topics: Animals; Blood Platelets; Humans; Lipid Metabolism; Lipids; Lipoproteins, HDL; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists
PubMed: 33804754
DOI: 10.3390/ijms22063180 -
Prostaglandins, Leukotrienes, and... Jan 2019Shortly after the discovery that linoleic acid was an essential fatty acid in 1930, α-linolenic acid also was reported to prevent the fatty acid deficiency syndrome in... (Review)
Review
Shortly after the discovery that linoleic acid was an essential fatty acid in 1930, α-linolenic acid also was reported to prevent the fatty acid deficiency syndrome in animals. However, several prominent laboratories could not confirm the findings with α-linolenic acid, and as a result there was a loss of interest in omega-3 fatty acids in lipid research. Even the findings that a prostaglandin can be synthesized from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is necessary for optimum retinal function generated only limited interest in omega-3 fatty acids. The breakthrough came in the 1970s when Dyerberg and Bang reported that the low incidence of atherosclerotic coronary disease in Greenland Eskimos was due to the high marine lipid content of their diet. They subsequently found that EPA, which was increased in Eskimo plasma, inhibited platelet aggregation, and they concluded that the low incidence of coronary artery disease was due to the anti-thrombotic effect of EPA. This stimulated widespread interest and research in EPA and DHA, leading to the present view that, like their omega-6 counterparts, omega-3 fatty acids have important physiological functions and are essential fatty acids.
Topics: Animals; Arachidonic Acid; Biomedical Research; Coronary Artery Disease; Coronary Thrombosis; Diet; Fatty Acids, Omega-3; Fibrinolytic Agents; Humans; Inuit; Linoleic Acid; Platelet Aggregation; Rats
PubMed: 30553403
DOI: 10.1016/j.plefa.2018.11.017 -
Scientific Reports Apr 2019Although reversible platelet aggregation observed in response to ADP stimulation in the presence of calcium is a well-known phenomenon, its mechanisms are not entirely...
Although reversible platelet aggregation observed in response to ADP stimulation in the presence of calcium is a well-known phenomenon, its mechanisms are not entirely clear. To study them, we developed a simple kinetic mass-action-law-based mathematical model to use it in combination with experiments. Light transmission platelet aggregometry (LTA) induced by ADP was performed for platelet-rich plasma or washed platelets using both conventional light transmission and aggregate size monitoring method based on optical density fluctuations. Parameter values of the model were determined by means of parameter estimation techniques implemented in COPASI software. The mathematical model was able to describe reversible platelet aggregation LTA curves without assuming changes in platelet aggregation parameters over time, but with the assumption that platelet can enter the aggregate only once. In the model, the mean size of platelet aggregates correlated with the solution transparency. This corresponded with flow cytometry analysis and with optical density fluctuations data on aggregate size. The predicted values of model parameters correlated with ADP concentration used in experiments. These data suggest that, at the start of the aggregation, when platelet integrins switch "on", large unstable platelet aggregates are rapidly formed, which leads to an increase in light transmission. However, upon fragmentation of these aggregates, the probability of the post-aggregate platelets' attachment to each other decreases preventing new aggregation and resulting in the reversible aggregation phenomenon.
Topics: Adenosine Diphosphate; Adolescent; Adult; Blood Platelets; Female; Flow Cytometry; Healthy Volunteers; Humans; Kinetics; Light; Male; Models, Theoretical; Platelet Aggregation; Platelet Function Tests; Scattering, Radiation; Software; Young Adult
PubMed: 30996289
DOI: 10.1038/s41598-019-42701-0 -
International Journal of Molecular... Jun 2018In oncotherapy, ruthenium (Ru) complexes are reflected as potential alternatives for platinum compounds and have been proved as encouraging anticancer drugs with high... (Review)
Review
In oncotherapy, ruthenium (Ru) complexes are reflected as potential alternatives for platinum compounds and have been proved as encouraging anticancer drugs with high efficacy and low side effects. Cardiovascular diseases (CVDs) are mutually considered as the number one killer globally, and thrombosis is liable for the majority of CVD-related deaths. Platelets, an anuclear and small circulating blood cell, play key roles in hemostasis by inhibiting unnecessary blood loss of vascular damage by making blood clot. Platelet activation also plays a role in cancer metastasis and progression. Nevertheless, abnormal activation of platelets results in thrombosis under pathological settings such as the rupture of atherosclerotic plaques. Thrombosis diminishes the blood supply to the heart and brain resulting in heart attacks and strokes, respectively. While currently used anti-platelet drugs such as aspirin and clopidogrel demonstrate efficacy in many patients, they exert undesirable side effects. Therefore, the development of effective therapeutic strategies for the prevention and treatment of thrombotic diseases is a demanding priority. Recently, precious metal drugs have conquered the subject of metal-based drugs, and several investigators have motivated their attention on the synthesis of various ruthenium (Ru) complexes due to their prospective therapeutic values. Similarly, our recent studies established that novel ruthenium-based compounds suppressed platelet aggregation via inhibiting several signaling cascades. Our study also described the structure antiplatelet-activity relationship (SAR) of three newly synthesized ruthenium-based compounds. This review summarizes the antiplatelet activity of newly synthesized ruthenium-based compounds with their potential molecular mechanisms.
Topics: Animals; Blood Platelets; Humans; Molecular Targeted Therapy; Organometallic Compounds; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Ruthenium; Thrombosis
PubMed: 29925802
DOI: 10.3390/ijms19061818 -
Journal of the American Heart... Apr 2018Vascular complications and abnormal platelet function contribute to morbidity and mortality in diabetes mellitus. We hypothesized that the Rho-related GTPase protein,...
BACKGROUND
Vascular complications and abnormal platelet function contribute to morbidity and mortality in diabetes mellitus. We hypothesized that the Rho-related GTPase protein, Rac1, can influence both endothelial and platelet function and might represent a potential novel therapeutic target in diabetes mellitus.
METHODS AND RESULTS
We used both in vitro and ex vivo approaches to test the effects of pharmacological inhibition of Rac1 during hyperglycemic condition. We evaluated the effect of NSC23766, a pharmacological inhibitor of Rac1, on vascular function in diabetic mice and platelet aggregation in diabetic subjects. We demonstrated that the administration of NSC23766 protects from hyperglycemia-induced endothelial dysfunction, restoring NO levels, and reduces oxidative stress generated by nicotinamide adenine dinucleotide phosphate oxidase. Mechanistically, we identified Rho-associated coiled-coil serine/threonine kinase-1 as a downstream target of Rac1. Moreover, we reported that during hyperglycemic conditions, human platelets showed hyperactivation of Rac1 and impaired NO release, which were both partially restored after NSC23766 treatment. Finally, we characterized the antiplatelet effect of NSC23766 during hyperglycemic conditions, demonstrating the additional role of Rac1 inhibition in reducing platelet aggregation in diabetic patients treated with common antiplatelet drugs.
CONCLUSIONS
Our data suggest that the pharmacological inhibition of Rac1 could represent a novel therapeutic strategy to reduce endothelial dysfunction and platelet hyperaggregation in diabetes mellitus.
Topics: Aminoquinolines; Animals; Blood Glucose; Blood Platelets; Diabetes Mellitus, Experimental; Endothelium, Vascular; Female; Humans; Male; Mice; Middle Aged; Platelet Activation; Platelet Aggregation; Pyrimidines; Vasodilation; rac1 GTP-Binding Protein
PubMed: 29626150
DOI: 10.1161/JAHA.117.007322 -
PloS One 2018Cutibacterium (Propionibacterium) acnes, considered a part of the skin microbiota, is one of the most commonly isolated anaerobic bacteria from medical implants in...
Cutibacterium (Propionibacterium) acnes, considered a part of the skin microbiota, is one of the most commonly isolated anaerobic bacteria from medical implants in contact with plasma. However, the precise interaction of C. acnes with blood cells and plasma proteins has not been fully elucidated. Herein, we have investigated the molecular interaction of C. acnes with platelets and plasma proteins. We report that the ability of C. acnes to aggregate platelets is dependent on phylotype, with a significantly lower ability amongst type IB isolates, and the interaction of specific donor-dependent plasma proteins (or concentrations thereof) with C. acnes. Pretreatment of C. acnes with plasma reduces the lag time before aggregation demonstrating that pre-deposition of plasma proteins on C. acnes is an important step in platelet aggregation. Using mass spectrometry we identified several plasma proteins deposited on C. acnes, including IgG, fibrinogen and complement factors. Inhibition of IgG, fibrinogen or complement decreased C. acnes-mediated platelet aggregation, demonstrating the importance of these plasma proteins for aggregation. The interaction of C. acnes and platelets was visualized using fluorescence microscopy, verifying the presence of IgG and fibrinogen as components of the aggregates, and co-localization of C. acnes and platelets in the aggregates. Here, we have demonstrated the ability of C. acnes to activate and aggregate platelets in a bacterium and donor-specific fashion, as well as added mechanistic insights into this interaction.
Topics: Blood Proteins; Humans; Mass Spectrometry; Microscopy, Fluorescence; Platelet Activation; Platelet Aggregation; Propionibacterium acnes
PubMed: 29385206
DOI: 10.1371/journal.pone.0192051