Platelet Transcriptome Profiling in HIV and ATP-Binding Cassette Subfamily C Member 4 (ABCC4) as a Mediator of Platelet Activity

Marcantoni, Emanuela; Allen, Nicole; Cambria, Matthew R.; Dann, Rebecca; Cammer, Michael; Lhakhang, Tenzin; O’Brien, Meagan P.; Kim, Benjamin; Worgall, Tilla S.; Heguy, Adriana; Tsirigos, Aristotelis; Berger, Jeffrey S.

doi:10.1016/j.jacbts.2017.10.005

Cited by 32 publications

(25 citation statements)

References 80 publications

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“…Accordingly, our results show lower RANTES secretion by thrombin-stimulated platelets from HIV-infected individuals even under stable ART. Similarly, reduced staining for platelet dense-granules has been recently reported in HIV-infected subjects compared to healthy volunteers 53 , suggesting that platelet dense-granules are also exhausted in HIV infection. In contrast to the lower platelet degranulation in response to thrombin, increased aggregation response due to ADP, collagen or arachidonic acid stimulation was reported in platelets from HIV-infected individuals under stable antiretroviral treatment 54 .…”

Section: Discussionmentioning

confidence: 61%

Persistent platelet activation and apoptosis in virologically suppressed HIV-infected individuals

Mesquita

Hottz

Amâncio

et al. 2018

Sci Rep

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Cardiovascular diseases and thrombotic events became major clinical problems in the combined antiretroviral therapy (cART) era. Although the precise mechanisms behind these clinical problems have not been fully elucidated, a persistent pro-inflammatory state plays a central role. As platelets play important roles on both, thrombus formation and inflammatory/immune response, we aimed at investigating platelet function in HIV-infected subjects virologically controlled through cART. We evaluate parameters of activation, mitochondrial function and activation of apoptosis pathways in platelets from 30 HIV-infected individuals under stable cART and 36 healthy volunteers. Despite viral control achieved through cART, HIV-infected individuals exhibited increased platelet activation as indicated by P-selectin expression and platelet spreading when adhered on fibrinogen-coated surfaces. Platelets from HIV-infected subjects also exhibited mitochondrial dysfunction and activation of apoptosis pathways. Finally, thrombin stimuli induced lower levels of P-selectin translocation and RANTES secretion, but not TXA2 synthesis, in platelets from HIV-infected individuals compared to control; and labeling of platelet alpha granules showed reduced granule content in platelets from HIV-infected individuals when compared to healthy subjects. In summary, platelets derived from HIV-infected individuals under stable cART exhibit a phenotype of increased activation, activation of the intrinsic pathway of apoptosis and undermined granule secretion in response to thrombin.

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Section: Discussionmentioning

confidence: 61%

Persistent platelet activation and apoptosis in virologically suppressed HIV-infected individuals

Mesquita

Hottz

Amâncio

et al. 2018

Sci Rep

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“…Here, Marcantoni et al. (1) report that the transcriptomes in platelets from PLWH are altered compared to those of platelets from HIV-uninfected individuals. The authors show that transcript and protein expression of ABCC4 are increased in platelets from PLWH compared with levels in platelets from uninfected subjects and that ABCC4 expression was related to markers of platelet activation (i.e., CD62P and PAC-1).…”

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confidence: 91%

“…In this issue of JACC: Basic to Translational Science , Marcantoni et al. (1) describe alterations in the transcriptomes of platelets from persons infected with the human immunodeficiency virus (HIV) compared with platelet transcriptomes from uninfected subjects. These changes in mRNA transcript levels have functional consequences on platelet activation.…”

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confidence: 99%

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Transcriptional Profiling Identifies Mechanisms Associated With Platelet Activation in HIV Infection

Funderburg

2018

JACC: Basic to Translational Science

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“…Most recently, impaired platelet aggregation in response to ADP was observed in ABCC4 null individuals [10]. Platelets with MRP4 overexpression, such as those obtained from subjects with human immunodeficiency virus (HIV), have reduced cytosolic cAMP levels [11].…”

Section: Introductionmentioning

confidence: 99%

MRP4 over-expression has a role on both reducing nitric oxide-dependent antiplatelet effect and enhancing ADP induced platelet activation

Guarino

Massimi

Alemanno

et al. 2020

J Thromb Thrombolysis

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The impact of inhibition of multidrug resistance protein 4 (MRP4) on nitric oxide (NO) resistance and on ADP-induced platelet aggregation is unknown. The aim of this investigation was to verify whether platelet NO resistance correlates with MRP4 expression and evaluate whether this can be reduced by in vitro MRP4 inhibition mediated by cilostazol. Moreover, we assessed if inhibition of MRP4-mediated transport reduces ADP-induced platelet reactivity. The inhibitory effect of sodium nitroprusside (SNP), a NO-donor that enhances cyclic guanosine monophosphate (cGMP) cytosolic concentration, was assessed in platelets obtained from aspirin treated patients and in a control population. The inhibitory effect of SNP was evaluated by ADP-induced aggregation in SNP-treated platelets. The impact of MRP4 on ADP-induced platelet aggregation was performed in high on aspirin residual platelet reactivity (HARPR) patients and compared to healthy volunteers (HV), and a control cohort (CTR). In aspirin-treated patients with high levels of MRP4, reduced SNP inhibition was found compared to those with low levels of MRP4. MRP4 inhibition by cilostazol significantly reduced ADP-induced platelet aggregation in HARPR population, and to a lesser extent in HV and CTR populations. In conclusion, cilostazol can mitigate the hyperreactive platelet phenotype of HARPR patients by reducing residual ADP-induced platelet aggregation and increasing NOdependent endothelial antiplatelet effects.

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Platelet Transcriptome Profiling in HIV and ATP-Binding Cassette Subfamily C Member 4 (ABCC4) as a Mediator of Platelet Activity

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Cited by 32 publications

References 80 publications

Persistent platelet activation and apoptosis in virologically suppressed HIV-infected individuals

Persistent platelet activation and apoptosis in virologically suppressed HIV-infected individuals

Transcriptional Profiling Identifies Mechanisms Associated With Platelet Activation in HIV Infection

MRP4 over-expression has a role on both reducing nitric oxide-dependent antiplatelet effect and enhancing ADP induced platelet activation

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