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58
Protective role of endothelial progenitor cells stimulated by riociguat in chronic thromboembolic pulmonary hypertension ☆ , ☆☆
Keiko Yamamoto
a,⁎ , Rintaro Nishimura
a, Fumiaki Kato
b, Akira Naito
a, Rika Suda
a, Ayumi Sekine
a, Takayuki Jujo
a, Ayako Shigeta
a, Seiichiro Sakao
a, Nobuhiro Tanabe
a, Koichiro Tatsumi
aaDepartment of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
bDepartment of Respirology, Hamamatsu Medical Center, 432-8580, 328, Tomitsuka-cho, Naka-ku, Hamamatsu-shi, Japan
a b s t r a c t a r t i c l e i n f o
Article history:
Received 2 March 2019
Received in revised form 6 June 2019 Accepted 4 July 2019
Available online 15 July 2019
Background:Pulmonary endothelial damage has a negative impact on the maintenance of normal pulmonary vas- cular function. Such damage results in delayed thrombus dissolution and vascular remodeling in chronic throm- boembolic pulmonary hypertension (CTEPH). Although endothelial progenitor cells (EPCs) may be incorporated into neovasculature during vascular repair, their function in CTEPH remains unclarified, especially under the aug- mentation of soluble guanylate cyclase (sGC) activity.
Methods and results:We evaluated the effect of EPCs on endothelial function and compared the effect of riociguat, a sGC stimulator, on the number and function of circulating EPCs in two groups of CTEPH patients. The two groups consisted 16 CTEPH patients who were treatment naïve (Naïve group), and 14 CTEPH patients who were being treated with riociguat, a sGC stimulator (Riociguat group). The number of circulating EPCs in the Riociguat group was significantly higher than that in the Naïve group. Gene expression levels associated with an- giogenesis were significantly higher in EPCs of the Riociguat group. EPC-stimulated tube formation and migration of human pulmonary microvascular endothelial cell (hPMVEC) in the Riociguat group exceeded that in the Naïve group. The angiogenic ability of hPMVECs stimulated by EPCs in the Riociguat group was enhanced compared to that of the sGC stimulator, BAY 41–2272.
Conclusion:Thesefindings indicate that riociguat may induce EPCs to play a protective role via modulation of en- dothelial functions associated with CTEPH.
Translation aspect of the work:Endothelial dysfunction exacerbates CTEPH. Riociguat enhanced the protective role of EPCs via neovascularization, which prevented vascular remodeling and alleviated CTEPH.
© 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords:
Chronic thromboembolic pulmonary hyper- tension
Soluble guanylate cyclase Endothelial progenitor cells Angiogenesis
1. Introduction
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and progressive disease. It is characterized by organized thrombi that obstruct pulmonary arteries and cause small vessel dis- ease, similar to those present in pulmonary arterial hypertension (PAH) [1,2]. Medical treatment of CTEPH targets vasodilation. How- ever, pulmonary vascular remodeling is also an important therapeu- tic target in CTEPH. Endothelial repair mechanisms including
angiogenesis may play a crucial role in vascular remodeling. There- fore, detailed investigations of pulmonary endothelial functions, and their association with vascular injury and repair, may lead to therapeutic benefits to CTEPH patients.
Endothelial progenitor cells (EPCs), derived from the bone mar- row, enter peripheral circulation to participate in re- endothelialization or neovascularization of damaged vessels, either directly or through paracrine effects [3]. However, controversial findings, such as EPC dysfunction as well as EPC participation in vas- cular remodeling, have been reported in PAH [4,5]. Reportedly, the number of circulating EPCs is elevated in PAH patients treated with vasodilators [4,6]. However, neither the function of circulating EPCs nor the effect of treatment on EPCs have been satisfactorily eluci- dated in PAH or CTEPH.
Pulmonary vasodilators are commonly used in both PAH and CTEPH.
It has been reported that vasodilators including phosphodiesterase 5 in- hibitor (PDE5i), soluble guanylate cyclase (sGC) stimulator, and the endothelin receptor antagonist (ERA) have augmented endothelial function [7], and prevented vascular remodeling in rat PAH models [8].
International Journal of Cardiology 299 (2020) 263–270
☆ Statement of Authorship: The authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
☆☆Acknowledgement of grant support: This study was supported in part by a grant from the Respiratory Failure Research Group of the Ministry of Health, Labor, and Welfare of Japan [H26-Intractable Diseases-General-076], a grant from the Pulmonary Hypertension Research Group from the Japan Agency for Medical Research and Development, AMED [15ek0109127h0001], and by JSPS KAKENHI [JP19K17665].
⁎ Corresponding author at: Department of Respirology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba 260-8670, Japan.
E-mail address:[email protected](K. Yamamoto).
https://doi.org/10.1016/j.ijcard.2019.07.017
0167-5273/© 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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