Antithrombotic actions of statins involve PECAM-1 signaling

Moraes, Leonardo A.; Vaiyapuri, Sakthivel; Sasikumar, Parvathy; Ali, Marfoua S.; Kriek, Neline; Sage, Tanya; Gibbins, Jonathan M.

doi:10.1182/blood-2013-04-491845

Cited by 39 publications

(23 citation statements)

References 43 publications

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“…Statins have antiplatelet effects in vitro, ex vivo, in animal models and in patients293239. Therefore, in order to distinguish their effects on endothelial cells from those on platelets, we used washed platelets from healthy non-medicated volunteers for our experiments.…”

Section: Resultsmentioning

confidence: 99%

Weibel-Palade body size modulates the adhesive activity of its von Willebrand Factor cargo in cultured endothelial cells

Ferraro

Silva

Grimes

et al. 2016

Sci Rep

109

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Changes in the size of cellular organelles are often linked to modifications in their function. Endothelial cells store von Willebrand Factor (vWF), a glycoprotein essential to haemostasis in Weibel-Palade bodies (WPBs), cigar-shaped secretory granules that are generated in a wide range of sizes. We recently showed that forcing changes in the size of WPBs modifies the activity of this cargo. We now find that endothelial cells treated with statins produce shorter WPBs and that the vWF they release at exocytosis displays a reduced capability to recruit platelets to the endothelial cell surface. Investigating other functional consequences of size changes of WPBs, we also report that the endothelial surface-associated vWF formed at exocytosis recruits soluble plasma vWF and that this process is reduced by treatments that shorten WPBs, statins included. These results indicate that the post-exocytic adhesive activity of vWF towards platelets and plasma vWF at the endothelial surface reflects the size of their storage organelle. Our findings therefore show that changes in WPB size, by influencing the adhesive activity of its vWF cargo, may represent a novel mode of regulation of platelet aggregation at the vascular wall.

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Section: Resultsmentioning

confidence: 99%

Weibel-Palade body size modulates the adhesive activity of its von Willebrand Factor cargo in cultured endothelial cells

Ferraro

Silva

Grimes

et al. 2016

Sci Rep

109

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“…Lyn phosphorylates platelet-endothelial cell adhesion molecule 1 (PECAM1, CD31) within its immunoreceptor tyrosine-based inhibitory (ITIM) motif that inhibits platelet activation in response to collagen stimulation 30 . In the presence of the TYMP inhibitor KIN59 we found that inhibition of TYMP activity significantly increased tyrosine phosphorylated PECAM1 (Figure 4C), potentially from Lyn release.…”

Section: Resultsmentioning

confidence: 99%

Thymidine Phosphorylase Participates in Platelet Signaling and Promotes Thrombosis

Gigante

Pérez‐Pérez

et al. 2014

Circulation Research

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Rationale Platelets contain abundant thymidine phosphorylase (TYMP), which is highly expressed in diseases with high risk of thrombosis, such as atherosclerosis and type II diabetes. Objective Test the hypothesis that TYMP participates in platelet signaling and promotes thrombosis. Methods and Results By using a ferric chloride (FeCl3) induced carotid artery injury thrombosis model, we found time to blood flow cessation was significantly prolonged in Tymp−/− and Tymp+/− mice compared to wild type (WT) mice. Bone marrow transplantation and platelet transfusion studies demonstrated that platelet TYMP was responsible for the antithrombotic phenomenon in the TYMP deficient mice. Collagen-, collagen-related peptide (CRP)-, adenosine diphosphate-and/or thrombin-induced platelet aggregation were significantly attenuated in Tymp+/− and Tymp−/− platelets, and in WT or human platelets pretreated with TYMP inhibitor KIN59. Tymp deficiency also significantly decreased agonist-induced P-select in expression. TYMP contains an N-terminal SH3 domain binding proline-rich motif and forms a complex with the tyrosine kinases Lyn, Fyn and Yes in platelets. TYMP-associated Lyn was inactive in resting platelets, and TYMP trapped and diminished active Lyn after collagen stimulation. Tymp/Lyn double haploinsufficiency diminished the antithrombotic phenotype of Tymp+/− mice. TYMP deletion or inhibition of TYMP with KIN59 dramatically increased PECAM-1 tyrosine phosphorylation and diminished CRP or collagen induced AKT phosphorylation. In vivo administration of KIN59 significantly inhibited FeCl3 induced carotid artery thrombosis without affecting hemostasis. Conclusion TYMP participates in multiple platelet signaling pathways and regulates platelet activation and thrombosis. Targeting TYMP might be a novel anti-platelet and anti-thrombosis therapy.

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“…They effectively lower the cholesterol levels, thereby reducing the risk of ischemic heart disease, and stroke. They can also modify endothelial function, control inflammatory response, promote plaque stability, inhibit thrombus formation, reduce platelet aggregation, increase collagen and smooth muscle cells, and maintain a balance between prothrombotic and fibrinolytic mechanisms 5. These are used in the treatment of hyperlipidemia and act on the same pathway of bisphosphonates but on an earlier step.…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin, a double weapon in osteoporosis treatment: an experimental and clinical study

El-Nabarawi¹,

Elwakd

Salem

2017

DDDT

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ObjectiveThe aim of this study was to evaluate the effect of atorvastatin on the bone formation and resorption markers in ovariectomized rats (experimental study), and to study its effect on the bone mineral density (BMD) in postmenopausal osteoporotic women (clinical study).Materials and methodsThe study involved experimental and clinical aspects. In the experimental aspect, 42 female Wistar rats were divided into five groups: Group I (n=6; sham-operated), Group II (n=6; 1 mL of carboxymethyl cellulose [CMC] was administered orally), Group III (n=6; 20 mg/kg orally of atorvastatin was administered), Group IV (n=12; untreated ovariectomized [OVX] rats and served as a model of osteoporosis [OP]) and Group V (n=12; 20 mg/kg orally of atorvastatin was administered to ovariectomized rats). After 4 weeks, serum acid phosphatase, alkaline phosphatase, osteocalcin, total calcium and inorganic phosphorus were assessed. Then, 3 µm thickness lumbar and femur sections were examined using a light microscope to assess cortical thickness, trabecular area, numbers of osteoblasts and osteoclasts. In the clinical aspect, 85 post-menopausal osteoporotic females with recently detected hyperlipidemia participated in the study. Atorvastatin 40 mg/day, calcium carbonate 500 mg/day and vitamin D 800 international units were given to all patients for a period of 18 months. BMD was measured at the start and at the end of the study by dual-energy X-ray absorptiometry (DEXA).ResultsIn the experiment aspect, the biomarkers of bone remodeling were notably elevated in the OVX group. Administration of atorvastatin produced a significant decrease in the level of these bone metabolic markers. Atorvastatin significantly ameliorates osteoporotic changes induced by ovariectomy. In the clinical aspect, after 18 months the DEXA showed improvement in the T-score for the three measured zones; however, these changes were statistically significant only in the femoral neck area.ConclusionAtorvastatin was able to decrease the rate of bone metabolism and increase osteogenic activity. It has dual mode of action; both anabolic and antiresorptive effect on bone. This lipophilic statin member may act as a double weapon drug.

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Antithrombotic actions of statins involve PECAM-1 signaling

Cited by 39 publications

References 43 publications

Weibel-Palade body size modulates the adhesive activity of its von Willebrand Factor cargo in cultured endothelial cells

Weibel-Palade body size modulates the adhesive activity of its von Willebrand Factor cargo in cultured endothelial cells

Thymidine Phosphorylase Participates in Platelet Signaling and Promotes Thrombosis

Atorvastatin, a double weapon in osteoporosis treatment: an experimental and clinical study

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