Prostaglandin I2 induces apoptosis via upregulation of Fas ligand in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension

Akagi, Satoshi; Nakamura, Kazufumi; Matsubara, Hiromi; Kusano, Kengo; Kataoka, Noriyuki; Oto, Takahiro; Miyaji, Kohei; Miura, Aya; Ogawa, Aiko; Yoshida, Masashi; Ueda-Ishibashi, Hatsue; Yutani, Chikao; Ito, Hiroshi

doi:10.1016/j.ijcard.2011.09.004

Cited by 21 publications

(22 citation statements)

References 38 publications

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“…A prostacyclin analogue has an antiproliferative effect 21 and prostacyclin has proapoptotic effects. 13 The release time of drugs from NPs can be controlled by the molecular weight of PLGA, and incorporated BPS would therefore be slowly released from NPs with hydrolysis of PLGA. We previously reported that FITC NPs were incorporated into PAH PASMCs and remained in the PAH PASMCs for a long time.…”

Section: Discussionmentioning

confidence: 99%

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Intratracheal Administration of Prostacyclin Analogue–incorporated Nanoparticles Ameliorates the Development of Monocrotaline and Sugen-Hypoxia-induced Pulmonary Arterial Hypertension

Akagi

Nakamura

Matsubara

et al. 2016

Journal of Cardiovascular Pharmacology

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Abstract:Nanoparticles (NPs) have been used as novel drug delivery systems. Drug-incorporated NPs for local delivery might optimize the efficacy and minimize the side effects of drugs. Intravenous prostacyclin improves long-term survival in patients with pulmonary arterial hypertension (PAH), but it causes serious side effects such as catheter-related infections. We investigated the efficacy and safety of intratracheal administration of a prostacyclin analogue, beraprost (BPS), incorporated NPs in Sugen-hypoxia-normoxia and monocrotaline rat models of PAH and in human PAH pulmonary arterial smooth muscle cells (PASMCs). After a single administration, BPS NPs significantly decreased right ventricular pressure, right ventricular hypertrophy, and pulmonary artery muscularization in the 2 rat models. BPS NPs significantly improved the survival rate in the monocrotaline rat model. No infiltration of inflammatory cells, hemorrhage, or fibrosis was found in the liver, kidney, spleen, and heart after the administration of BPS NPs. No liver or kidney dysfunction was found in the blood examinations. BPS and BPS NPs significantly inhibited the proliferation of human PAH PASMCs after 24 hours of treatment. BPS NPs significantly continued to inhibit the proliferation of human PAH PASMCs at 24 hours after the removal of BPS NPs. BPS NPs significantly induced apoptosis in PAH PASMCs compared to that in non-PAH PASMCs. Intratracheal administration of BPS NPs ameliorates pulmonary hypertension in PAH rat models by a sustained antiproliferative effect and a proapoptotic effect on PAH PASMCs.

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Section: Discussionmentioning

confidence: 99%

“…Pulmonary artery smooth muscle cells (PASMCs) were used for the scheduled experiments at passage 6. 13 …”

Section: Methodsmentioning

confidence: 99%

Intratracheal Administration of Prostacyclin Analogue–incorporated Nanoparticles Ameliorates the Development of Monocrotaline and Sugen-Hypoxia-induced Pulmonary Arterial Hypertension

Akagi

Nakamura

Matsubara

et al. 2016

Journal of Cardiovascular Pharmacology

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“… 37 We have also reported that high-dose epoprostenol has a pro-apoptotic effect on PAH-PASMCs via the IP receptor and upregulation of Fas ligand (FasL) in vitro ( Figure 1 ). 38 In a case series, we examined the reverse pulmonary vascular remodeling effects of epoprostenol in lung tissues obtained from an IPAH patient treated with high-dose epoprostenol and an IPAH patient not treated with epoprostenol. 39 Apoptotic cells were detected in small pulmonary arteries of the IPAH patient treated with high-dose epoprostenol (115 ng/kg/min) but not in those from the IPAH patient not treated with epoprostenol.…”

Section: Reverse Remodeling Of Pulmonary Arteries By High-dose Epopromentioning

confidence: 99%

Epoprostenol sodium for treatment of pulmonary arterial hypertension

Saito¹,

Nakamura²,

Akagi³

et al. 2015

VHRM

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The release of endogenous prostacyclin (PGI2) is depressed in patients with pulmonary arterial hypertension (PAH). PGI2 replacement therapy by epoprostenol infusion is one of the best treatments available for PAH. Here, we provide an overview of the current clinical data for epoprostenol. Epoprostenol treatment improves symptoms, exercise capacity, and hemodynamics, and is the only treatment that has been shown to reduce mortality in patients with idiopathic PAH (IPAH) in randomized clinical trials. We have reported that high-dose epoprostenol therapy (>40 ng/kg/min) also results in marked hemodynamic improvement in some patients with IPAH. High-dose epoprostenol has a pro-apoptotic effect on PAH-PASMCs via the IP receptor and upregulation of Fas ligand (FasL) in vitro. However, long-term intravenous administration of epoprostenol is sometimes associated with catheter-related infections and leads to considerable inconvenience for the patient. In the future, the development of new routes of administration or the development of powerful PGI2 analogs, IP-receptor agonists, and gene and cell-based therapy enhancing PGI2 production with new routes of administration is required.

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“…Compared with the baseline state, high-dose epoprostenol therapy reduced mean pulmonary arterial pressure (mPAP) by 30% and PVR by 68%. We have also reported that high-dose epoprostenol has a pro-apoptotic effect on pulmonary artery smooth muscle cells (PASMCs) of patients with PAH via the IP receptor [10]. …”

Section: Prostacyclin Therapy For Pahmentioning

confidence: 99%

Nanoparticle-Mediated Drug Delivery System for Pulmonary Arterial Hypertension

Nakamura

Matsubara

Akagi

et al. 2017

JCM

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Nanoparticles have been used as a novel drug delivery system. Drug-incorporated nanoparticles for local delivery might optimize the efficacy and minimize the side effects of drugs. The efficacy and safety of intratracheal administration of prostacyclin analog (beraprost) -incorporated nanoparticles and imatinib (a PDGF-receptor tyrosine kinase inhibitor) -incorporated nanoparticles in Sugen-hypoxia-normoxia or monocrotaline rat models of pulmonary arterial hypertension (PAH) and in human PAH-pulmonary arterial smooth muscle cells have been reported. The use of inhaled drug-incorporated nanoparticles might be a novel approach for the treatment of PAH.

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Prostaglandin I2 induces apoptosis via upregulation of Fas ligand in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension

Cited by 21 publications

References 38 publications

Intratracheal Administration of Prostacyclin Analogue–incorporated Nanoparticles Ameliorates the Development of Monocrotaline and Sugen-Hypoxia-induced Pulmonary Arterial Hypertension

Intratracheal Administration of Prostacyclin Analogue–incorporated Nanoparticles Ameliorates the Development of Monocrotaline and Sugen-Hypoxia-induced Pulmonary Arterial Hypertension

Epoprostenol sodium for treatment of pulmonary arterial hypertension

Nanoparticle-Mediated Drug Delivery System for Pulmonary Arterial Hypertension

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