Activation of soluble guanylyl cyclase with inhibition of multidrug resistance protein inhibitor-4 (MRP4) as a new antiplatelet therapy

Mendes-Silvério, Camila B.; Lescano, Caroline Honaiser; Zaminelli, Tiago; Sollon, Carolina; Anhê, Gabriel Forato; Antunes, Edson; Mónica, Fabíola Z.

doi:10.1016/j.bcp.2018.03.028

Cited by 12 publications

(8 citation statements)

References 49 publications

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“…To specifically evaluate the impact of ABCC4 function on erythroid differentiation in the murine system, we inhibited ABCC4 function in Ent1 2/2 mice with MK-571. 55 Retro-orbital administration of MK-571 (10 mg/kg for 6 days) increased total RBCs, Hb, and hematocrit in Ent1 2/2 mice to levels similar to those detected in WT mice (Figure 6D). Interestingly though, MK-571 treatment did not alter red cell macrocytosis in Ent1 2/2 mice, strongly suggesting that erythropoiesis, but not macrocytosis, is regulated by ABCC4 in the absence of ENT1.…”

Section: Role Of Abcc4 In Cyclic Nucleotide Homeostasis In Ent1 Null ...supporting

confidence: 55%

“…Moreover, we find that inhibition of ABCC4 by MK-571 results in a rescue of the anemic phenotype in Ent1 2/2 mice, and an enhanced RBC production in WT mice without a significant reduction in circulating white blood cells. Notably, MK-571 has been tested in clinical trials as a therapeutic molecule to treat asthma, [68][69][70] pulmonary arterial hypertension, 71 and platelet aggregation 55,72,73 via increasing the intracellular levels of cAMP and cGMP. The impact of MK-571 in pulmonary arterial hypertension was specific to its effects on ABCC4 because deletion of this gene resulted in a notable reduction in hypoxia-induced inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

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The equilibrative nucleoside transporter ENT1 is critical for nucleotide homeostasis and optimal erythropoiesis

Mikdar

González-Menéndez

Cai

et al. 2021

Blood

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The tight regulation of intracellular nucleotides is critical for the self-renewal and lineage specification of hematopoietic stem cells (HSCs). Nucleosides are major metabolite precursors for nucleotide biosynthesis and their availability in HSCs is dependent on their transport through specific membrane transporters. However, the role of nucleoside transporters in the differentiation of HSCs to the erythroid lineage and in red cell biology remains to be fully defined. Here, we show that the absence of the equilibrative nucleoside transporter (ENT1) in human red blood cells (RBCs) with a rare Augustine-null blood type (AUG:-1) is associated with macrocytosis, anisopoikilocytosis, an abnormal nucleotide metabolome, and deregulated protein phosphorylation. A specific role for ENT1 in human erythropoiesis was demonstrated by a defective erythropoiesis of human CD34+ progenitors following shRNA-mediated knockdown of ENT1. Furthermore, genetic deletion of ENT1 in mice was associated with reduced erythroid progenitors in the bone marrow, anemia and macrocytosis. Mechanistically, we found that ENT1-mediated adenosine transport is critical for cAMP homeostasis and the regulation of erythroid transcription factors. Notably, genetic investigation of two ENT1null individuals demonstrated a compensation by a loss-of-function variant in the ABCC4 cyclic nucleotide exporter. Indeed, pharmacological inhibition of ABCC4 in Ent1-/- mice rescued erythropoiesis. Overall, our results highlight the importance of ENT1-mediated nucleotide metabolism in erythropoiesis.

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Section: Role Of Abcc4 In Cyclic Nucleotide Homeostasis In Ent1 Null ...supporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

The equilibrative nucleoside transporter ENT1 is critical for nucleotide homeostasis and optimal erythropoiesis

Mikdar

González-Menéndez

Cai

et al. 2021

Blood

View full text Add to dashboard Cite

show abstract

“…These results are in total accordance with previous studies showing that the inhibition of ABCC4 leads to a decrease in human platelet function, and that an inhibitor of ABCC4 (MK 571) can be used as a therapeutic molecule to potentiate the aggregating effects of some guanylate cyclase activators usually used in thrombotic complications. 34 The role of ABCC4 in platelet function has also been demonstrated in ABCC4-deficient mice in which the cytosolic level of cAMP in platelets is higher than in wild-type mice. 10,11 In malignant diseases, ABC transporters contribute to chemotherapy resistance because of their drug efflux capabilities in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Lack of the multidrug transporter MRP4/ABCC4 defines the PEL-negative blood group and impairs platelet aggregation

Azouzi

Mikdar

Hermand

et al. 2020

Blood

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The rare PEL-negative phenotype is one of the last blood groups with an unknown genetic basis. By combining whole-exome sequencing and comparative global proteomic investigations, we found a large deletion in the ABCC4/MRP4 gene encoding an ATP-binding cassette (ABC) transporter in PEL-negative individuals. The loss of PEL expression on ABCC4-CRISPR-Cas9 K562 cells and its overexpression in ABCC4-transfected cells provided evidence that ABCC4 is the gene underlying the PEL blood group antigen. Although ABCC4 is an important cyclic nucleotide exporter, red blood cells from ABCC4null/PEL-negative individuals exhibited a normal guanosine 3′,5′-cyclic monophosphate level, suggesting a compensatory mechanism by other erythroid ABC transporters. Interestingly, PEL-negative individuals showed an impaired platelet aggregation, confirming a role for ABCC4 in platelet function. Finally, we showed that loss-of-function mutations in the ABCC4 gene, associated with leukemia outcome, altered the expression of the PEL antigen. In addition to ABCC4 genotyping, PEL phenotyping could open a new way toward drug dose adjustment for leukemia treatment.

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“…A recent work by Mendes-Silverio et al [31] suggests that MRP4 plays an additional role in platelets. BAY 60-2770 is a soluble guanylyl cyclase activator that potently inhibits human platelet aggregation and adhesion through overstimulation of the cGMP-PKG signaling pathway [32].…”

Section: The Role Of Mrp4 In Plateletsmentioning

confidence: 98%

Multidrug resistance-associated protein 4 in pharmacology: Overview of its contribution to pharmacokinetics, pharmacodynamics and pharmacogenetics

et al. 2019

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Activation of soluble guanylyl cyclase with inhibition of multidrug resistance protein inhibitor-4 (MRP4) as a new antiplatelet therapy

Cited by 12 publications

References 49 publications

The equilibrative nucleoside transporter ENT1 is critical for nucleotide homeostasis and optimal erythropoiesis

The equilibrative nucleoside transporter ENT1 is critical for nucleotide homeostasis and optimal erythropoiesis

Lack of the multidrug transporter MRP4/ABCC4 defines the PEL-negative blood group and impairs platelet aggregation

Multidrug resistance-associated protein 4 in pharmacology: Overview of its contribution to pharmacokinetics, pharmacodynamics and pharmacogenetics

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