mTORC1 promotes aging-related venous thrombosis in mice via elevation of platelet volume and activation

Yang, Jun; Zhou, Xuan; Fan, Xiaoning; Xiao, Min; Yang, Dian; Liang, Bo; Dai, Meng; Shan, Lanlan; Lu, Jing-Bo; Lin, Zhiqi; Liu, Rong; Li, Jun; Wang, Liping; Zhong, Ming; Jiang, Yu; Bai, Xia

doi:10.1182/blood-2015-10-672964

Cited by 73 publications

(47 citation statements)

References 48 publications

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“…Each year, 1.1 million Americans experience acute myocardial infarction. Another million experience a thrombotic cerebrovascular accident, and DVT (deep vein thrombosis) is a major problem for surgical and other hospitalized patients [1,2,5,49,50]. However, current antithrombotic agents have serious side effects, mainly bleeding episodes [6].…”

Section: Discussionmentioning

confidence: 99%

“…Thrombosis-related diseases, such as myocardial infarction, stroke, and venous thromboembolism, account for substantial morbidity and mortality in the United States and developed countries [1,2]. Furthermore, thrombosis is the leading cause of morbidity and mortality in patients with diabetes mellitus, with a reported 65% of diabetic patients eventually dying from thrombotic diseases [3].…”

Section: Introductionmentioning

confidence: 99%

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Xanthohumol isolated from Humulus lupulus prevents thrombosis without increased bleeding risk by inhibiting platelet activation and mtDNA release

Xin

Wei

et al. 2017

Free Radical Biology and Medicine

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Aim As the global population has reached 7 billion and the baby boom generation reaches old age, thrombosis has become the major contributor to the global disease burden. It has been reported that, in moderate doses, beer may protect against thrombosis. Xanthohumol (XN), an antioxidant, is found at high concentrations in hop cones (Humulus lupulus L.) and is a common ingredient of beer. Here, the aim of the present work was to investigate the effects of XN on antithrombotic and antiplatelet activities, and study its mechanism. Approach and Results Using ferric chloride-induced carotid artery injury, inferior vena cava ligation model, and platelet function tests, we demonstrated that XN uniquely prevents both venous and arterial thrombosis by inhibiting platelet activation. Interestingly, in tail bleeding time studies, XN did not increase bleeding risk, which is recognized as a major limitation of current antithrombotic therapies. We also demonstrated that XN induces Sirt1 expression and thereby decreases reactive oxygen species (ROS) overload, prevents mitochondrial dysfunction, and reduces activated platelet-induced mitochondrial hyperpolarization, respiratory disorders, and associated membrane damage at low concentrations. In mitochondrial function assays designed to detect amounts of extracellular mitochondrial DNA (mtDNA), we found that XN prevents mtDNA release, which induces platelet activation in a DC-SIGN-dependent manner. Conclusions XN exemplifies a promising new class of antiplatelet agents that are highly effective at inhibiting platelet activation by decreasing ROS accumulation and platelet mtDNA release without incurring a bleeding risk. This study has also provided novel insights into mechanisms of thrombotic diseases with possible therapeutic implications.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Xanthohumol isolated from Humulus lupulus prevents thrombosis without increased bleeding risk by inhibiting platelet activation and mtDNA release

Xin

Wei

et al. 2017

Free Radical Biology and Medicine

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“…The GADOLIN data were updated with 10 months of additional follow-up and 17 more patients 43. The safety profile was consistent with that of the primary analysis.…”

Section: Developmentmentioning

confidence: 67%

The clinical development of obinutuzumab for the treatment of follicular lymphoma

Ma¹,

Ujjani

2017

CMAR

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Impressive progress has been made in recent decades for advanced-stage follicular lymphoma with the availability of anti-CD20 monoclonal antibodies, initially rituximab and more recently obinutuzumab. Obinutuzumab is a unique, third-generation, fully humanized glycoengineered IgG1 type II anti-CD20 monoclonal antibody. It has been shown to have increased antitumor activity compared to rituximab in preclinical studies, including whole-blood B-cell depletion assays, xenograft models, and primate models. This has spurred on the development of obinutuzumab through Phase I/II trials as monotherapy and in combination with chemotherapeutic agents and other targeted therapies. Its efficacy compared to rituximab and in rituximab-refractory disease has led to its continued development and eventual approval for the treatment of follicular lymphoma. Here in this review, we highlight the design and development of obinutuzumab in the treatment of advanced stage grade 1–3A follicular lymphoma and its future directions.

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“…Larger platelet size, measured as increased mean platelet volume (MPV), is a risk factor for cardiovascular disease CVD . MPV increases with age in mice, which might explain the increasing CVD risk in the elderly . Circumstantial evidence suggests that large platelets are more active, but there is yet no direct evidence for this and why this may be so.…”

Section: Introductionmentioning

confidence: 99%

Activation‐induced changes in platelet surface receptor expression and the contribution of the large‐platelet subpopulation to activation

Moroi

Farndale

Jung

2020

Research and Practice in Thrombosis and Haemostasis

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Objective Platelet surface receptors are also present subcellularly in organelle membranes and can be expressed on the surface upon platelet activation. However, some receptors were reported to be decreased after activation. We analyzed the mechanism of activation‐dependent expression for different receptors. Methods Flow cytometry using platelet‐rich plasma or washed platelets was used to analyze receptor‐expression changes after platelet activation by glycoprotein (GP) VI–specific agonists, crosslinked collagen‐related peptide (CRP‐XL) and convulxin (Cvx), and thrombin. Platelets prelabeled with fluorescent antibody specific for a receptor were allowed to adhere on immobilized collagen or fibrinogen and post‐stained with antibody against the same receptor labeled with another fluorophore, allowing us to differentiate preexisting receptors from newly expressed receptors. Results Surface expression of αIIbβ3 increased in CRP‐XL–, Cvx‐, or thrombin‐stimulated platelets, but GPIb decreased due to shedding and internalization. Both total and dimeric GPVI increased in thrombin‐induced platelets, but decreased in platelets stimulated by Cvx, as a result of internalization. The larger platelets showed a greater increase in surface receptor (α2β1, αIIbβ3, GPVI, GPIb) expression upon activation compared to the smaller ones. Pre‐ and postlabeling with antibody specific for the same receptor, but conjugated with different fluorophores, allowed us to differentiate the receptors expressed on the surface of resting platelets from receptors newly exposed to the surface upon platelet activation. Conclusions Increased receptor expressions after activation are mainly manifested in the larger platelets. On platelets adhered on fibrinogen, the newly expressed receptors, especially GPVI, are localized in the lamellipodia of the spread platelets.

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mTORC1 promotes aging-related venous thrombosis in mice via elevation of platelet volume and activation

Abstract: Key Points Activation of mTORC1 in MKs and platelets contributes to aging-related venous thrombosis. ROS production with aging activates mTORC1 to elevate MPV and platelet activation and promote venous thrombosis.

Cited by 73 publications

References 48 publications

Xanthohumol isolated from Humulus lupulus prevents thrombosis without increased bleeding risk by inhibiting platelet activation and mtDNA release

Xanthohumol isolated from Humulus lupulus prevents thrombosis without increased bleeding risk by inhibiting platelet activation and mtDNA release

The clinical development of obinutuzumab for the treatment of follicular lymphoma

Activation‐induced changes in platelet surface receptor expression and the contribution of the large‐platelet subpopulation to activation

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