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Resistance to thromboembolism in PI3Kgamma-deficient mice
1Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, Via Santina 5 bis, 10126 Turin, Italy. emilio.hirsch@unito.it
Insights
Phosphoinositide 3-kinase gamma (PI3Kgamma) plays a key role in adenosine diphosphate (ADP)-induced platelet aggregation, a critical factor in thrombosis. Targeting PI3Kgamma may offer a novel antithrombotic therapy for ischemic diseases.
Area of Science:
- Cardiovascular Biology
- Hematology
- Molecular Pharmacology
Background:
- Platelet aggregation and thrombosis are primary causes of ischemic events like heart attack and stroke.
- Adenosine diphosphate (ADP) signaling through G protein-coupled receptors (GPCRs) is crucial for thrombus formation.
- Phosphoinositide 3-kinases (PI3K) are involved in ADP-mediated platelet activation.
Purpose of the Study:
- To investigate the specific role of the PI3Kgamma isoform in ADP-induced platelet aggregation and thrombosis.
- To determine the downstream signaling pathways affected by PI3Kgamma deficiency in platelets.
- To evaluate the therapeutic potential of targeting PI3Kgamma for antithrombotic strategies.
Main Methods:
- Utilized PI3Kgamma-deficient mice to assess platelet aggregation responses.
- Stimulated platelets with ADP, collagen, and thrombin to compare responses.
- Measured protein kinase B (PKB/Akt) phosphorylation and alpha(IIb)beta(3) fibrinogen receptor activation.
- Assessed bleeding times and survival rates in response to ADP-induced thromboembolism.
Main Results:
- ADP-induced platelet aggregation was significantly impaired in PI3Kgamma-deficient mice.
- Collagen or thrombin stimulation evoked normal platelet aggregation in these mice.
- PI3Kgamma deficiency led to reduced PKB/Akt phosphorylation and alpha(IIb)beta(3) activation upon ADP stimulation.
- PI3Kgamma-null mice showed protection against lethal ADP-induced thromboembolism without affecting bleeding time.
Conclusions:
- PI3Kgamma plays a specific and critical role downstream of ADP in platelet activation and thrombus formation.
- Pharmacological inhibition of PI3Kgamma presents a promising therapeutic avenue for preventing ADP-mediated thrombosis and ischemic diseases.
- This study elucidates a novel, targeted approach for antithrombotic therapy.
Abstract:
Platelet aggregation and subsequent thrombosis are the major cause of ischemic diseases such as heart attack and stroke. ADP, acting via G protein-coupled receptors (GPCRs), is an important signal in thrombus formation and involves activation of phosphoinositide 3-kinases (PI3K). When platelets from mice lacking the G protein-activated PI3Kgamma isoform were stimulated with ADP, aggregation was impaired. Collagen or thrombin, however, evoked a normal response. ADP stimulation of PI3Kgamma-deficient platelets resulted in decreased PKB/Akt phosphorylation and alpha(IIb)beta(3) fibrinogen receptor activation. These effects did not influence bleeding time but protected PI3Kgamma-null mice from death caused by ADP-induced platelet-dependent thromboembolic vascular occlusion. This result demonstrates an unsuspected, well-defined role for PI3Kgamma downstream of ADP and suggests that pharmacological targeting of PI3Kgamma has a potential use as antithrombotic therapy.