Reduced thrombus stability in mice lacking the α2A-adrenergic receptor

Požgajová, Miroslava; Sachs, Ulrich J.; Hein, Lutz; Nieswandt, Bernhard

doi:10.1182/blood-2005-12-4835

Cited by 64 publications

(42 citation statements)

References 37 publications

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“…(4) While other groups have shown that PM can cause the activation of platelets (49), we have not been able to detect this in our model (4). In mice, epinephrine alone is unable to promote platelet shape change or aggregation (50)(51)(52)(53), but it may potentiate the effect of known activators of platelets such as adenosine diphosphate (ADP) (51,54,55). Therefore, while a PM-induced increase in platelet number or activity may contribute to the development of ischemic cardiovascular events in humans, catecholamine-induced changes in platelet numbers or activation alone are unlikely to explain the effects of catecholamines in our model (56).…”

Section: Discussioncontrasting

confidence: 44%

β2-Adrenergic agonists augment air pollution–induced IL-6 release and thrombosis

Chiarella¹,

Soberanes²,

Urich³

et al. 2014

J. Clin. Invest.

114

101

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Acute exposure to particulate matter (PM) air pollution causes thrombotic cardiovascular events, leading to increased mortality rates; however, the link between PM and cardiovascular dysfunction is not completely understood. We have previously shown that the release of IL-6 from alveolar macrophages is required for a prothrombotic state and acceleration of thrombosis following exposure to PM. Here, we determined that PM exposure results in the systemic release of catecholamines, which engage the β 2 -adrenergic receptor (β 2 AR) on murine alveolar macrophages and augment the release of IL-6. In mice, β 2 AR signaling promoted the development of a prothrombotic state that was sufficient to accelerate arterial thrombosis. In primary human alveolar macrophages, administration of a β 2 AR agonist augmented IL-6 release, while the addition of a beta blocker inhibited PM-induced IL-6 release. Genetic loss or pharmacologic inhibition of the β 2 AR on murine alveolar macrophages attenuated PM-induced IL-6 release and prothrombotic state. Furthermore, exogenous β 2 AR agonist therapy further augmented these responses in alveolar macrophages through generation of mitochondrial ROS and subsequent increase of adenylyl cyclase activity. Together, these results link the activation of the sympathetic nervous system by β 2 AR signaling with metabolism, lung inflammation, and an enhanced susceptibility to thrombotic cardiovascular events.

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Section: Discussioncontrasting

confidence: 44%

β2-Adrenergic agonists augment air pollution–induced IL-6 release and thrombosis

Chiarella¹,

Soberanes²,

Urich³

et al. 2014

J. Clin. Invest.

114

101

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“…11 Under the threshold concentration of collagen with epinephrine as an agonist, the effect of many alpha 2-adrenoceptor antagonists on platelet aggregation has been explored. 10,[12][13][14] We used yohimbine (a standard alpha 2 adrenoceptor antagonist) as a comparator control and measured the degree of platelet aggregation at baseline and 5 h which was compared with cleistanthins A and B. Even though the half-life of yohimbine is 0.6 h, it produces ten times more potent active metabolite called 11-OH yohimbine with a half-life of 6-7 h. 15 Hence the effect of yohimbine could be observed even after 5 h. In our study, yohimbine at 2 mg/kg dose has shown a significant inhibition of platelet aggregation after 5 h by blocking alpha 2-adrenoceptor in platelet.…”

Section: Discussionmentioning

confidence: 99%

Action of Cleistanthins A and B on Alpha Adrenoceptors in Rats

Lakshmanan¹,

Bobby²,

Raveendran³

2016

JYP

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Objectives: Cleistanthins A and B (CAB), active phytochemicals present in Cleistanthus collinus, have been proven to have alpha 1-adrenoceptor blocking property. However action on alpha 2-adrenoceptor is not studied. We aimed to study the action of CAB on alpha 2-adrenoceptor by measuring platelet aggregation, insulin and blood glucose levels with yohimbine as a standard comparator control and alpha 1-adrenoceptor by measuring the blockade of relaxation induced by phenylephrine in the jejunum of Wistar albino rats. Materials and methods: Forty eight adult male Wistar rats were divided into eight drug groups of six each, namely control (CMC 0.5%), yohimbine 2 mg/kg, 10, 30 and 100 mg/kg doses of cleistanthin A and cleistanthin B. Blood samples were drawn at baseline, after 5 h and after high-epinephrine dose (5 mg/kg) from the retro-orbital sinus and used for estimation of platelet aggregation and plasma insulin levels. Blood glucose levels were estimated at six different time points. Degree of jejunal relaxation was studied by relaxing the acetylcholine pre-contracted jejunum with phenylephrine. Results: All groups, except control and cleistanthin A 10 mg/kg group, significantly inhibited the platelet aggregation when compared to the respective baseline values (p<0.05). No significant difference was observed between different drug groups in plasma insulin and blood glucose levels. With regard to phenylephrine induced jejunal relaxation, the median IC 50 for all three doses of cleistanthin A and cleistanthin B 100 mg/kg differ significantly from that of control (CMC 0.5%). Conclusion: CAB block both alpha 1 and 2-adrenoceptorand hence are non-selective alpha-adrenoceptor blockers.

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“…In two in vivo models of thrombosis, FeCl3 induced injury of mesenteric arterioles and mechanical firm compression of the aorta, α2A-adrenergic-deficient mice displayed increased embolus formation suggesting a certain degree of thrombus instability. 80 Variable responsiveness to epinephrine in relation to factors such as age, strenuous exercise or pathological conditions such as heart disease or myeloproliferative syndromes has been related to changes in the platelet expression level of α2A-adrenergic receptors. 81,82 Some polymorphisms in the α2A-adrenergic receptor influence in vitro shear mediated platelet function.…”

confidence: 99%

Platelet receptors and signaling in the dynamics of thrombus formation

Rivera¹,

Lozano²,

et al. 2009

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Hemostasis and pathological thrombus formation are dynamic processes that require a co-ordinated series of events involving platelet membrane receptors, bidirectional intracellular signals, and release of platelet proteins and inflammatory substances. This review aims to summarize current knowledge in the key steps in the dynamics of thrombus formation, with special emphasis on the crucial participation of platelet receptors and signaling in this process. Initial tethering and firm adhesion of platelets to the exposed subendothelium is mediated by glycoprotein (GP) Ib/IX/V complex and collagen receptors, GP VI and α2β1 integrin, in the platelet surface, and by VWF and fibrillar collagen in the vascular site. Interactions between these elements are largely influenced by flow and trigger signaling events that reinforce adhesion and promote platelet activation. Thereafter, soluble agonists, ADP, thrombin, TxA2, produced/released at the site of vascular injury act in autocrine and paracrine mode to amplify platelet activation and to recruit circulating platelets to the developing thrombus. Specific interactions of these agonists with their G-protein coupled receptors generate inside-out signaling leading to conformational activation of integrins, in particular αIIbβ3, increasing their ligand affinity. Binding of αIIbβ3 to its ligands, mainly fibrinogen, supports processes such as clot retraction and platelet aggregation. Stabilization of thrombi is supported by the late wave of signaling events promoted by close contact between aggregated platelets. The best known contact-dependent signaling is outside-in signaling through αIIbβ3, but new ones are being clarified such as those mediated by interaction of Eph receptors with ephrins, or by Sema 4D and Gas-6 binding to their receptors. Finally, newly identified mechanisms appear to control thrombus growth, including back-shifting of activated integrins and actuation of compensatory molecules such as ESAM or PECAM-1. The expanding knowledge of thrombotic disease is expected to translate into the development of new drugs to help management and prevention of thrombosis.Key words: platelet, receptors, thrombus formation.Citation: Rivera J, Lozano ML, Navarro-Núñez L, Vicente V. Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica 2009; 94:700-711. doi:10.3324/haematol.2008 This is an open-access paper. ABSTRACT Platelet receptors and signaling in the dynamics of thrombus formationJosé Rivera, María Luisa Lozano, Leyre Navarro-Núñez, and Vicente Vicente Unit of Hematology and Clinical Oncology, Centro Regional de Hemodonación, University of Murcia, Spain © F e r r a t a S t o r t i F o u n d a t i o nand metastasis, or immunological host defense. 1Internally, platelets contain a cytoskeleton, a dense tubular system, few mitochondrias, glycogen granules, dense (δ) and α storage granules and peroxisomes. The α-granules retain relevant proteins for the hemostatic function of platelets, such as von Willebrand factor (VWF), fibrinogen, P-selectin,...

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Reduced thrombus stability in mice lacking the α2A-adrenergic receptor

Cited by 64 publications

References 37 publications

β2-Adrenergic agonists augment air pollution–induced IL-6 release and thrombosis

β2-Adrenergic agonists augment air pollution–induced IL-6 release and thrombosis

Action of Cleistanthins A and B on Alpha Adrenoceptors in Rats

Platelet receptors and signaling in the dynamics of thrombus formation

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