Activation of Peroxisome Proliferator-Activated Receptor α in Megakaryocytes Reduces Platelet-Derived Growth Factor-BB in Platelets

Hashizume, Shunji; Akiyama, Masashi; Azuma, Hiroyuki; Ishikawa, Kazue; Yoshida, Sumiko; Sumitomo-Ueda, Yuka; Yagi, Shusuke; Ikeda, Yasumasa; Igarashi, Takashi; Aihara, Ken‐ichi; Abe, Masahiro; Sata, Masataka; Matsumoto, Toshio

doi:10.5551/jat.5868

Cited by 10 publications

(8 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The transcriptional effect on megakaryocytes, responsible for platelet gene expression adaptome , was previously showed, in fact transcriptional change that can be transmitted to circulating platelets is evident for PPARα activation in human bone marrow megakaryocytes 6, 21…”

Section: Resultsmentioning

confidence: 96%

MiR‐21 role in aspirin‐dependent PPARα and multidrug resistance protein 4 upregulation

Massimi

Alemanno

Guarino

et al. 2018

Research and Practice in Thrombosis and Haemostasis

View full text Add to dashboard Cite

BackgroundA mechanism involved in high on‐aspirin treatment residual platelet reactivity is platelet multidrug resistance protein 4 (MRP4) overexpression. Aspirin enhances platelet MRP4 expression with a PPARα‐dependent mechanism and reduces miR‐21 expression that, in turn, downregulates PPARα expression.ObjectiveThe aim of our study was to verify the relationship between miR‐21 and MRP4‐PPARα levels induced by aspirin treatment.MethodsWe evaluated the changes in MRP4‐PPARα, mRNA, MRP4 protein, and miR‐21 expression induced by aspirin in: (i) in vitro–treated megakaryoblastic cell line (DAMI), (ii) primary megakaryocytes cultures and derived platelets, (iii) healthy volunteers’ platelets treated with aspirin, and (iv) aspirinated patients (aspirin‐treated patients) and in a control population (control).ResultsWe observed an aspirin‐induced reverse relationship between the expression of miR‐21 and PPARα‐MRP4. In DAMI cells the miR‐21 mimic transfection reduces PPARα and MRP4 expression, even if cells were treated with aspirin after transfection. MiR‐21 inhibitor transfection induces PPARα and MRP4 expression that are not enhanced by aspirin treatment. In human megakaryocytes, aspirin treatment lead to a miR‐21 downregulation and a MRP4 upregulation and this trend is confirmed in derived platelets. In aspirin‐treated volunteers, an inverse relationship between miR‐21 and MRP4 platelet expression was found after aspirin treatment. A similar negative relationship was found in aspirin‐treated patients vs the control population.ConclusionThe results reported in this study provide information that aspirin induces the modulation of platelet miR‐21 expression levels and this modulation can be responsible for MRP4 enhancement in circulating platelets.

show abstract

Section: Resultsmentioning

confidence: 96%

MiR‐21 role in aspirin‐dependent PPARα and multidrug resistance protein 4 upregulation

Massimi

Alemanno

Guarino

et al. 2018

Research and Practice in Thrombosis and Haemostasis

View full text Add to dashboard Cite

show abstract

“…First, our study verifies that circulating galectin-3 was significantly higher in AMI patients than in normal controls. Inflammation and oxidative stress [34][35][36] play a key role in all stages of atherosclerosis and vascular remodeling, from initiation, progression of athermanous plaques and luminal narrowing, finally leading to acute coronary syndromes 11,31) as a consequence of plaque rupture. Interestingly, galectin-3 has been shown to be an important contributor to inflammation 6,16) .…”

Section: Independent Predictors Of 30-day Maco (Table 6)mentioning

confidence: 99%

Value and Level of Galectin-3 in Acute Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention

Tsai

Sung

Chang

et al. 2012

J Atheroscler Thromb

View full text Add to dashboard Cite

Aim: This study investigated the impact of the circulating galectin-3 level on the 30-day prognostic outcome in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).Results: The galectin-3 level was determined using ELISA. Our results demonstrated that the circulating level of galectin-3 was significantly higher in STEMI patients than in healthy control subjects (p＜0.001). As compared with patients with galectin-3 ＜7.67 ng/mL, patients with galectin-3 ≥ 7.67 ng/mL were significantly older, had significantly lower left ventricular ejection fraction and significantly higher frequency of elevated white blood cell count, advanced Killip score (defined as ≥ score 3), congestive heart failure (defined as ≥ New York Heart Association Functional Class Ⅲ), respiratory failure, unstable hemodynamics requiring a mechanical ventilator and intra-aortic balloon pump support, multiple vessel diseases and 30-day mortality (all p＜0.04). Furthermore, multivariate analysis showed that elevated circulating level of galectin-3 was the strongest independent predictor of the combined 30-day major adverse clinical outcome (MACO) (defined as advanced CHF or 30-day mortality) (p＜0.0001). Conclusion: A high circulating galectin-3 level may serve as a useful biomarker for predicting 30-day MACO in patients with STEMI undergoing primary PCI.

show abstract

“…Human bone marrow megakaryocytes (MKs) express PPARα, as well as platelets, and its activation can decrease PDGF‐BB expression, both in MKs and in platelets .…”

Section: Introductionmentioning

confidence: 99%

Aspirin influences megakaryocytic gene expression leading to up‐regulation of multidrug resistance protein‐4 in human platelets

Massimi

Guerriero

Lotti

et al. 2014

Brit J Clinical Pharma

View full text Add to dashboard Cite

AimThe aim of the study was to investigate whether human megakaryocytic cells have an adaptive response to aspirin treatment, leading to an enhancement of multidrug resistance protein-4 (MRP4) expression in circulating platelets responsible for a reduced aspirin action. We recently found that platelet MRP4 overexpression has a role in reducing aspirin action in patients after by-pass surgery. Aspirin enhances MRP4-mRNA levels in rat liver and drug administration transcriptionally regulates MRP4 gene expression through peroxisome proliferator-activated receptor-α (PPARα).MethodsThe effects induced by aspirin or PPARα agonist (WY14643) on MRP4 modulation were evaluated in vitro in a human megakaryoblastic DAMI cell line, in megakaryocytes (MKs) and in platelets obtained from human haematopoietic progenitor cell (HPC) cultures, and in vivo platelets obtained from aspirin treated healthy volunteers (HV).ResultsIn DAMI cells, aspirin and WY14643 treatment induced a significant increase in MRP4 and PPARα expression. In human MKs grown in the presence of either aspirin or WY14643, MRP4 and PPARα-mRNA were higher than in control cultures and derived platelets showed an enhancement in MRP4 protein expression. The ability of aspirin to modulate MRP4 expression in MKs and to transfer it to platelets was also confirmed in vivo. In fact, we found the highest MRP4 mRNA and protein expression in platelets obtained from HV after 15 days' aspirin treatment.ConclusionsThe present study provides evidence, for the first time, that aspirin treatment affects the platelet protein pattern through MK genomic modulation. This work represents an innovative and attractive approach, useful both to identify patients less sensitive to aspirin and to improve pharmacological treatment in cardiovascular high-risk patients.

show abstract

Activation of Peroxisome Proliferator-Activated Receptor α in Megakaryocytes Reduces Platelet-Derived Growth Factor-BB in Platelets

Cited by 10 publications

References 31 publications

MiR‐21 role in aspirin‐dependent PPARα and multidrug resistance protein 4 upregulation

MiR‐21 role in aspirin‐dependent PPARα and multidrug resistance protein 4 upregulation

Value and Level of Galectin-3 in Acute Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention

Aspirin influences megakaryocytic gene expression leading to up‐regulation of multidrug resistance protein‐4 in human platelets

Contact Info

Product

Resources

About