Increased levels of platelet-derived microparticles in pulmonary hypertension

doi:10.1016/j.thromres.2020.07.030

Thrombosis Research

Volume 195, November 2020, Pages 120-124

https://doi.org/10.1016/j.thromres.2020.07.030 Get rights and content

Highlights

•
Pulmonary hypertension patients have high levels of platelet derived microparticles.
•
Higher platelet derived microparticle level in male idiopathic pulmonary arterial hypertension
•
Higher dose of epoprostenol tended to lower platelet derived microparticle levels.

Abstract

Introduction

Thrombosis and coagulation abnormalities are thought to be involved in disease progression of pulmonary hypertension. Platelet-derived microparticles (PDMP) are released from platelets following stimulation and have recently been demonstrated to play an important role in pathogenesis of various diseases. This study aimed to evaluate PDMP levels in patients with pulmonary hypertension.

Materials and methods

Our cross-sectional study enrolled a total of 113 participants including 73 patients with pulmonary hypertension and 40 participants to serve as a control group. PDMP levels were measured using a PDMP ELISA kit, which detects glycoproteins CD42a and CD42b. Clinical parameters, including exercise capacity and hemodynamic parameters, were collected, and the relationship to PDMP levels were evaluated.

Results

PDMP levels were significantly higher in patients than in participants in the control group (23.2 ± 39.4 U/mL and 7.8 ± 3.6 U/mL, respectively, P < 0.05). PDMP levels in patients with chronic thromboembolic pulmonary hypertension were correlated with right atrial pressure and cardiac index. PDMP levels were higher in male patients with idiopathic pulmonary arterial hypertension. Furthermore, patients administered a higher dose of epoprostenol had a tendency for lower PDMP levels.

Conclusions

The data suggest that PDMP levels are increased in patients with pulmonary hypertension. Further study is needed to understand the mechanism and impact of PDMP on disease progression.

Introduction

Pulmonary hypertension remains a fatal disease despite the development of various drugs in the past decades. It is characterized by increased pulmonary vascular resistance due to pulmonary vascular remodeling [1]. Not all mechanisms that cause pulmonary hypertension have been identified. Thrombosis is considered to be involved in pathogenesis in many types of pulmonary hypertension. In pulmonary arterial hypertension (PAH), thrombosis in the microvasculature is reported to be in the small pulmonary arteries [2]. Pulmonary hypertension is associated with a hypercoagulable phenotype that includes upregulation of tissue factor, an increase in circulating levels of Von Willebrand factor, and abnormal platelet aggregation [[3], [4], [5], [6]]. Acute pulmonary embolism is considered to be a provoking factor in chronic thromboembolic pulmonary hypertension (CTEPH) [1,7].

In many pathological conditions such as vascular diseases, atherosclerosis, diabetes, and cancer, the number of microparticles is increased. Microparticles are small (0.1 to 1 μm) membrane-derived vesicles that are generated from cells through activation or apoptosis [8]. Although red blood cells, leukocytes, or endothelial cells can release microparticles, most of the microparticles found in the blood originate from platelets (platelet-derived microparticles [PDMP]) and are released following stimulation. Recent findings have revealed that PDMP plays an important role in many physiological and pathological processes. Several groups reported that increased numbers of circulating PDMP were found in PAH patients [9,10].

In this study, we aimed to evaluate PDMP levels in patients with pulmonary hypertension and investigate its relationship to clinical parameters.

Section snippets

Study population

We enrolled a total of 113 subjects including 73 patients with pulmonary hypertension and 40 participants to serve as a control group. A diagnosis of pulmonary hypertension was made based on a detailed medical history, a physical examination, chest radiography, a chest computed tomography scan, transthoracic echocardiography, lung ventilation-perfusion scintigraphy, and right heart catheterization [11]. PAH categories were as follows: idiopathic PAH (IPAH) (n = 24), associated PAH (connective

PDMP levels in all participants

Baseline demographics of patients with pulmonary hypertension and control participants are shown in Table 1. Approximately 80% of the patients were female. At the time of venous sampling, 70% of the patients were in WHO functional class II, and 6MWD was approximately 350 m. Mean pulmonary arterial pressure (mPAP) was slightly less than 40 mm Hg. PDMP levels were significantly higher in patients with pulmonary hypertension than in healthy participants (P < 0.05). Among healthy participants,

Discussion

In this study, we measured plasma levels of PDMP in 73 patients with various subgroups of pulmonary hypertension. This is the largest report on PDMP levels measured in patients with pulmonary hypertension and found that PDMP levels are increased compared to those of control subjects. Patients with CTD showed the highest levels of PDMP. It was previously reported that levels of PDMP were high in patients with CTD, regardless of whether complicated by pulmonary hypertension [13]. After excluding

Funding

This study was supported, in part, by research grants from JSPS KAKENHI Grant-in-Aid for Young Scientists (B) 25860632, Takeda Science Foundation, Japan Heart Foundation/Novartis Grant for Research Award on Molecular and Cellular Cardiology 2013, GSK Japan Research Grant 2014, and the Okayama Medical Foundation.

Declaration of competing interest

A.O. received lecture fees from Bayer Yakuhin, Ltd.; Pfizer Japan, Inc.; Nippon Shinyaku, Co, Ltd.

H.M. received lecture fees from AOP Orphan Pharmaceuticals AG; Bayer Yakuhin, Ltd.; Pfizer Japan, Inc.; Nippon Shinyaku, Co, Ltd.; Actelion Pharmaceuticals Japan, Ltd.; GlaxoSmithKline K.K.; and Kaneka Medix Corporation.

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Most platelets are present in peripheral blood, but some are stored in the spleen. Because the tissue environments of peripheral blood vessels and the spleen are quite distinct, the properties of platelets present in each may also differ. However, no studies have addressed this difference. We previously reported that hypothermia activates splenic platelets, but not peripheral blood platelets, whose biological significance remains unknown. In this study, we focused on platelet-derived microvesicles (PDMVs) and analyzed their biological significance connected to intrasplenic platelet activation during hypothermia.
C57Bl/6 mice were placed in an environment of −20 °C, and their rectal temperature was decreased to 15 °C to model hypothermia. Platelets and skeletal muscle tissue were collected and analyzed for their interactions.
Transcriptomic changes between splenic and peripheral platelets were greater in hypothermic mice than in normal mice. Electron microscopy and real-time RT-PCR analysis revealed that platelets activated in the spleen by hypothermia internalized transcripts, encoding tissue repairing proteins, into PDMVs and released them into the plasma. Plasma microvesicles from hypothermic mice promoted wound healing in the mouse myoblast cell line C2C12. Skeletal muscles in hypothermic mice were damaged but recovered within 24 h after rewarming. However, splenectomy delayed recovery from skeletal muscle injury after the mice were rewarmed.
These results indicate that PDMVs released from activated platelets in the spleen play an important role in the repair of skeletal muscle damaged by hypothermia.
Hypoxia-activated platelets stimulate proliferation and migration of pulmonary arterial smooth muscle cells by phosphatidylserine/LOX-1 signaling-impelled intercellular communication
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Citation Excerpt :
Then we exposed LOX-1−/− rats to hypoxia for 21 days and found that LOX-1−/− rats demonstrated significant protection from hypoxic PH, including amelioration of hemodynamics, right ventricular hypertrophy (RVH) and pulmonary vascular remodeling (Fig. 2A–I). In many types of PH patients, inappropriate activity and continuous recruitment of platelets have been reported, including hypoxic PH [6,21,22]. In this study, to further confirm the inappropriate activity and continuous recruitment of platelets in hypoxic PH rats, we extracted platelets from SD rats by magnetic cell separation system and marked platelets with CD45-PE and CD61-FITC to detect the purity by flow cytometry.
Continuous recruitment and inappropriate activation of platelets in pulmonary arteries contribute to pulmonary vascular remodeling in pulmonary hypertension (PH). Our previous study has demonstrated that lectin like oxidized low-density lipoprotein receptor-1 (LOX-1) regulates the proliferation of pulmonary arterial smooth muscle cells (PASMCs). Phosphatidylserine exposed on the surface of activated platelets is a ligand for LOX-1. However, whether hypoxia-activated platelets stimulate the proliferation and migration of PASMCs by phosphatidylserine/LOX-1 signaling-impelled intercellular communication remains unclear. The present study found that rats treated with hypoxia (10% O₂) for 21 days revealed PH with the activation of platelets and the recruitment of platelets in pulmonary arteries, and LOX-1 knockout inhibited hypoxia-induced PH and platelets activation. Notably, co-incubation of PASMCs with hypoxic PH rats-derived platelets up-regulated LOX-1 expression in PASMCs leading to the proliferation and migration of PASMCs, which was inhibited by the phosphatidylserine inhibitor annexin V or the LOX-1 neutralizing antibody. LOX-1 knockout led to decreased proliferation and migration of PASMCs stimulated by hypoxia-activated platelets. In rats, hypoxia up-regulated the phosphorylation of signal transducer and activator of transcription 3 (Stat3) and the expression of Pim-1 in pulmonary arteries. Hypoxia-activated platelets also up-regulated the phosphorylation of Stat3 and the expression of Pim-1 in PASMCs, which was inhibited by annexin V, the LOX-1 neutralizing antibody, the protein kinase C inhibitor and LOX-1 knockout. In conclusion, we for the first time demonstrated that hypoxia-activated platelets stimulated the proliferation and migration of PASMCs by phosphatidylserine/LOX-1/PKC/Stat3/Pim-1 signaling-impelled intercellular communication, thereby potentially contributing to hypoxic pulmonary vascular remodeling.
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Extracellular vesicles in venous thromboembolism and pulmonary hypertension
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Full Length ArticleIncreased levels of platelet-derived microparticles in pulmonary hypertension

Highlights

Abstract

Introduction

Materials and methods

Results

Conclusions

Introduction

Section snippets

Study population

PDMP levels in all participants

Discussion

Funding

Declaration of competing interest

Chest

Journal of the American College of Cardiology

Drug Discov Today

Thromb Res

The American journal of cardiology

Eur Heart J

Primary pulmonary hypertension: natural history and the importance of thrombosis

Circulation

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Nature reviews. Cardiology

Plexiform-like lesions and increased tissue factor expression in a rat model of severe pulmonary arterial hypertension

Am J Physiol Lung Cell Mol Physiol

Abnormal platelet aggregation in idiopathic pulmonary arterial hypertension: role of nitric oxide

Am J Physiol Lung Cell Mol Physiol

Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism

The New England journal of medicine

Cell-derived microparticles in haemostasis and vascular medicine

Thromb Haemost

Cellular microparticles in the pathogenesis of pulmonary hypertension

The European respiratory journal

Small platelet microparticle levels are increased in pulmonary arterial hypertension

Eur J Clin Invest

Full Length Article
Increased levels of platelet-derived microparticles in pulmonary hypertension