Journal of Cardiology 78 (2021) 1–11

Contents lists available at ScienceDirect

Journal of Cardiology
journal homepage: www.elsevier.com/locate/jjcc

Review

Drug discovery focused on novel pathogenic proteins for pulmonary

arterial hypertension
Kimio Satoh (MD, PhD, FJCC)
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Pulmonary arterial hypertension (PAH) is a fatal disease in which the wall thickening and narrowing
Received 24 December 2020 of pulmonary microvessels progress due to complicated interactions among processes such as endothe-
Accepted 24 December 2020
lial dysfunction, the proliferation of pulmonary artery smooth muscle cells (PASMCs) and adventitial fi-
Available online 6 February 2021
brocytes, and inflammatory cell infiltration. Early diagnosis of patients with PAH is difficult and lung
Keywords: transplantation is the only last choice to save severely ill patients. However, the number of donors is
Pulmonary arterial hypertension limited. Many patients with PAH show rapid progression and a high degree of pulmonary arterial re-
Drug discovery modeling characterized by the abnormal proliferation of PASMCs, which makes treatment difficult even
Biomarker with multidrug therapy comprising pulmonary vasodilators. Thus, it is important to develop novel ther-
apy targeting factors other than vasodilation, such as PASMC proliferation. In the development of PAH,
inflammation and oxidative stress are deeply involved in its pathogenesis. Excessive proliferation and
apoptosis resistance in PASMCs are key mechanisms underlying PAH. Based on those characteristics, we
recently screened novel pathogenic proteins and have performed drug discovery targeting those proteins.
To confirm the clinical significance of this, we used patient-derived blood samples to evaluate biomarker
potential for diagnosis and prognosis. Moreover, we conducted high throughput screening and found sev-
eral inhibitors of the pathogenic proteins. In this review, we introduce the recent progress on basic and
clinical PAH research, focusing on the screening of pathogenic proteins and drug discovery.
© 2021 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Introduction velopment of cardiovascular diseases [25–27]. In addition, we iden-

Pulmonary arterial hypertension (PAH) is often overlooked
based on early symptoms, and in many cases, severe right heart
failure has already occurred at the time of visit to a specialized fa-
cility. There are no biomarkers for the early diagnosis of PAH, and
patients are often at the end of life when they are referred to a
specialized facility for lung transplantation [1,2]. Lung transplanta-
tion is the final choice for critically ill patients, but the number
of donors is limited. In patients with advanced stage, the prog-
nosis is poor even with the use of pulmonary vasodilators, and
thus, the development of essential therapeutic agents is awaited
[3,4]. We have been conducting basic and clinical research on pul-
monary hypertension for many years [5–15]. To date, we have dis-
covered novel pathogenic proteins involved in pulmonary hyper-
tension and are proceeding with drug discovery and biomarker de-
velopment [16–19]. Specifically, we have elucidated the crucial role
of erythropoietin receptor in the pulmonary vascular endothelium
[20–24]. Endothelial dysfunction is regulated by many environ-
mental factors including nitric oxide and is important for the de-
E-mail address: satoh-k@cardio.med.tohoku.ac.jp
tified cyclophilin A (CyPA), which is secreted by pulmonary artery
smooth muscle cells (PASMCs) under oxidative stress, and eluci-
dated its importance in the progression of pulmonary hyperten-
sion [16,28]. Furthermore, we identified novel pathogenic proteins
for pulmonary hypertension and confirmed their roles using genet-
ically modified mice [11,17–19,29–31]. Moreover, we successfully
performed high-throughput screening of inhibitors against these
pathogenic proteins [11,17,19,30–33].
PASMCs from patients with PAH (PAH-PASMCs) are highly pro-
liferative, like cancer cells, and cause pulmonary arterial wall thick-
ening [34]. Therefore, based on the inhibitory effect of PAH-PASMC
proliferation, we conducted drug discovery screening with the
support of the Japan Agency for Medical Research and Develop-
ment, Drug Discovery Initiative (DDI), and the Tohoku University
Graduate School of Pharmaceutical Sciences. We performed high-
throughput screening using the Tohoku University drug discovery
library of 5562 species and focused on PAH-PASMC growth inhi-
bition as an index, finally identifying several compounds that are
effective in animal models of pulmonary hypertension [30,31,33].
Currently, with the support of the Platform for Advanced Tech-
nology Support for Drug Discovery (BINDS), we are evaluating the

https://doi.org/10.1016/j.jjcc.2021.01.009
0914-5087/© 2021 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
K. Satoh
Fig. 1. Screening of novel therapeutic targets for pulmonary arterial hypertension (PAH).
PAH-PASMCs, pulmonary artery smooth muscle cells harvested from patients with PAH. Figure adapted from Satoh et al. [34].
absorption, distribution, metabolism, and excretion, pharmacoki-
netics, and basic safety of the identified compounds. Furthermore,
with pharmaceutical companies, we are in the process of devel-
oping synthetic routes for these compounds, have succeeded in
obtaining final synthetic products, and have confirmed their in-
hibitory effects on PAH-PASMC proliferation.
To further elucidate the molecular mechanism that regulates
the abnormal proliferation of PAH-PASMCs, we performed compre-
hensive analyses of gene expression and various omics data and
found several novel pathogenic proteins for PAH (Fig. 1) [18,35].
In addition, using the core library of drug discovery mechanism,
we successfully screened low-molecular weight compounds that
suppress gene expression of the identified pathogenic proteins and
succeeded in identifying several types of compounds with efficacy
in animal models of pulmonary hypertension. In this way, with the
technical support of the DDI, Tohoku University Graduate School of
Pharmaceutical Sciences, and BINDS, we are proceeding with the
development of a completely new therapeutic drug based on the
suppression of PAH-PASMC proliferation. In addition to develop-
ing a novel biomarker for early PAH diagnosis, we have presented
the possibility of developing a novel therapy (companion diagnos-
tic/therapeutic drug) that can be used in combination. Accordingly,
with the goal of making pulmonary hypertension a disease that is
easily treatable with oral medication, we are trying to elucidate its
essential etiology and develop therapeutic agents [34]. In this re-
view, we introduce the recent progress in basic and translational
research related to this goal.
Cyclophilin A and Basigin
Hypoxia activates various signaling pathways including HIF-
1α and promotes PASMC proliferation [36–38]. Interestingly, PAH-
PASMCs exhibit the constitutive activation of HIF-1α even under
normoxic conditions, which is called “pseudohypoxia” and forms
the basis of a cancer-like growth mechanism [39,40]. Pseudohy-
poxia is a unique phenomenon in which cells exhibit a hypoxic
2
Journal of Cardiology 78 (2021) 1–11
phenotype even under normoxic conditions [41]. When mice are
maintained in a chronic hypoxic condition, thickening of the me-
dia and the adventitia in pulmonary arteries and pulmonary mi-
crovessel muscularization occur [5,11,20]. During this process, the
infiltration of various inflammatory cells is observed in the pul-
monary arteries, and inflammation of the pulmonary vessels plays
an important role in the development of pulmonary hypertension
[8,9,42]. Likewise, vascular inflammation is important for the de-
velopment of vascular diseases including atherosclerosis [6,43,44].
Importantly, we have found that excessive and chronic augmenta-
tion of oxidative stress promotes the secretion of CyPA from vas-
cular smooth muscle cells and inflammatory cells [45–49]. Addi-
tionally, secreted extracellular CyPA induces endothelial dysfunc-
tion [45,46,50,51]. Basigin (Bsg) is known as one of the extracellu-
lar CyPA receptors and is essential for the infection of erythrocytes
with malaria [52]. CyPA/Bsg signaling has a vascular endothelial-
activating action and disturbs the nitric oxide metabolism nec-
essary to maintain vascular homeostasis [47,53–55]. Bsg is also
called EMMPRIN [extracellular matrix metalloproteinase (MMP) in-
ducer] and promotes remodeling of the extracellular matrix via
MMP activation [56,57]. Therefore, Bsg activation by extracellular
CyPA might promote pulmonary vascular remodeling [58,59]. Thus,
we conducted studies using mice deficient in CyPA and Bsg genes
and confirmed that deficiencies in either gene made it difficult to
induce pulmonary hypertension [16]. Furthermore, we found that
the plasma levels of CyPA in patients with pulmonary hyperten-
sion are significantly higher than those in healthy subjects and that
this is a useful biomarker for prognosis [16]. Interestingly, plasma
CyPA concentration was also found to have long-term prognostic
value for patients with severe heart failure, such as that associ-
ated with post-capillary pulmonary hypertension [30]. Additionally,
we found that plasma levels of CyPA are useful biomarkers for the
therapeutic effect of balloon angioplasty on chronic thromboem-
bolic pulmonary hypertension [15]. However, we also found that
the CyPA receptor, Bsg, promotes cardiac hypertrophy and fibro-
sis under pressure-overload conditions induced by transverse aor-
K. Satoh Journal of Cardiology 78 (2021) 1–11

Fig. 2. Proposed mechanism of Bsg-mediated cardiac fibrosis and hypertrophy. Cyclic stretch and angiotensin II (AngII) promote cardiac fibroblast (CF) activation and prolif-
eration, which is mediated by cell surface basigin (Bsg). Bsg signaling activates Akt, ERK1/2, and SAPK in CFs and induces cell proliferation, oxidative stress, and inflammatory
cytokines, resulting in metalloproteinase (MMP) activation. The extracellular active form of MMPs cleave cell surface Bsg and release the soluble form of Bsg (sBsg), which
interacts with cell membrane Bsg again in an autocrine/paracrine manner. As a result, Bsg forms a feedback loop to augment the proliferation of CFs and inflammatory
cytokine secretion. Inflammatory cytokines and sBsg released from CFs stimulate cardiomyocyte hypertrophy and promote cardiac hypertrophy in a paracrine manner. Figure
adapted from Suzuki et al. [60].

tic ligation [60]. Indeed, Bsg is strongly expressed on the cell sur-
face of cardiac fibroblasts and cardiomyocytes [61–63]. In response
to stretch or angiotensin II, some Bsg on the surfaces of cardiac
fibroblasts is cleaved and released outside of the cell as soluble
Bsg [60]. This soluble Bsg promotes cell proliferation through the
extracellular stimulation of Bsg in cardiac fibroblasts and induces
hypertrophy signaling in adjacent cardiomyocytes (Fig. 2) [60]. Im-
portantly, the serum levels of soluble Bsg can predict the long-term
prognosis of patients with heart failure [60]. Thus, both CyPA and
Bsg are molecules that promote pulmonary hypertension, heart
failure, and myocardial fibrosis [48,64,65]. Based on this, we fur-
ther performed comprehensive screening of low-molecular weight
compounds that suppress both CyPA and Bsg with the support of
the DDI and Tohoku University Graduate School of Pharmaceutical
Sciences. As a result of high-throughput screening with the drug
discovery core library, we found that celastrol, a component iso-
lated from the root extracts of Tripterygium wilfordii, suppresses
the expression of CyPA and Bsg in PAH-PASMCs [30]. Moreover,
celastrol ameliorated the development of heart failure and post-
capillary pulmonary hypertension, resulting in a significant im-
provement in exercise tolerance in mice with pressure overload-
induced heart failure [30]. Thus, it is expected that celastrol could
be applied for the treatment of cardiovascular diseases in the fu-
ture.
Selenoprotein P
Various drugs to treat patients with PAH have become available.
However, currently available therapeutic agents for pulmonary hy-
pertension only target pulmonary vasodilatory effects [12]. In pa-
tients with severe PAH, a sufficient therapeutic effect cannot be ob-
tained even by combination therapy with vasodilators [66]. Since
the basis of PAH pathophysiology is the abnormal proliferation of
PASMCs, which is similar to that in cancer cells [40,67], the de-
velopment of therapeutic agents targeting their growth inhibition
will enable more effective treatment [1,68]. Thus, we have estab-
lished libraries of PAH-PASMCs, screened for novel pathogenic pro-
teins, and conducted drug screening targeting these proteins [34].
Through comprehensive analysis of lung tissues and PAH-PASMCs,
we selected candidate genes and novel proteins that were specif-
ically expressed in PAH-PASMCs and that augment cell prolifera-
tion (Fig. 1) [12,34,69]. After narrowing down the candidates, we
selected some pathogenic proteins in PAH and verified their roles
using genetically modified mice. Specifically, comprehensive gene
expression analysis was performed using PAH-PASMCs and PASMCs
derived from healthy subjects, and we discovered selenoprotein P
(SeP), which showed a marked increase in PAH-PASMCs (Fig. 3)
[18]. SeP is a unique secreted protein that contains many trace el-
ements, including selenium [70]. Approximately 65% is produced
in the liver under physiological conditions, and its main role is to
transport selenium to the peripheral organs [71]. However, it has
been reported that SeP is involved in insulin resistance in type 2
diabetes mellitus [72] and that an associated gene polymorphism
is involved in the development of abdominal aortic aneurysms
[73,74]. Furthermore, in the lung tissue of PAH patients, we found
a marked increase in the expression of SeP, especially in the thick-
ened peripheral pulmonary arterial media [18]. In addition, the “P”
of SeP indicates plasma [70]. Thus, we further evaluated plasma
levels of SeP in PAH patients and found that they were signifi-
cantly higher than those in healthy controls [35,75]. Based on these
clinical implications, we decided to further elucidate the signifi-
cance of SeP in the development of pulmonary hypertension us-
ing genetically modified mice [18]. Through analyses of vascular
smooth muscle cell-specific SeP knockout mice, hepatocyte-specific
SeP knockout mice, systemic SeP-overexpressing mice, and liver-
specific SeP-overexpressing mice, we demonstrated that SeP ex-
pression in the lung, but not in the liver, promotes the develop-
ment of pulmonary hypertension [18]. As a result of several ex-
aminations, such as the stimulation of PAH-PASMCs with purified
human plasma SeP, SeP knockdown by siRNA, and SeP overexpres-
sion, we confirmed that SeP itself promotes the abnormal prolifer-
ation of PAH-PASMCs. Mechanistically, extracellular SeP was found

3
K. Satoh
Fig. 3. Enhancement of SeP gene expression in PAH-PASMCs.
PAH, pulmonary arterial hypertension; PASMCs, pulmonary artery vascular smooth muscle cells; SeP, selenoprotein P. Figure adapted from Kikuchi et al. [18].
to suppress FOXO3a phosphorylation via its receptor, ApoER2, and
upregulate HIF-1α activities, comprising a feedback loop leading
to cell proliferation in PAH-PASMCs (Fig. 4). HIF-1α enhances ox-
idative stress by reducing glutathione, which is important to re-
lieve various forms of oxidative stress [11,41,76,77]. HIF-1α moves
into the nucleus and promotes the expression of various genes that
possess the hypoxia responsive elements [78]. Interestingly, we
found that SeP expression was affected by HIF-1α and ApoER2 ex-
pression in PAH-PASMCs [18]. In this way, comprehensive screening
using patient-derived specimens proved that SeP is a pathogenic
protein in PAH and a promising therapeutic target (Fig. 5). As
the next step, we conducted drug discovery screening for SeP in-
hibitors [18]. We carried out high-throughput screening using a
compound library consisting of existing drugs in the DDI. As a re-
sult, we discovered several low-molecular weight compounds, in-
cluding the plant alkaloid sanguinarine, as compounds that sup-
press SeP gene expression and thereby the abnormal growth of
PAH-PASMCs [18]. Indeed, these compounds were found to inhibit
SeP expression in the lungs in animal models of pulmonary hy-
pertension and had a therapeutic effect, which represents a com-
pletely new mechanism of PAH.
Based on the discovery of a novel causative protein of PAH [18],
we next started to develop a new measurement system for blood
SeP concentrations. In collaboration with Dr Saito at Doshisha Uni-
versity and Dr Misu at Kanazawa University, we finally developed
a system for the evaluation of SeP in the blood [35,75]. As there
was previously no specific biomarker, it was very difficult to di-
agnose patients with PAH in the early stages [79]. Delays in PAH
diagnosis and treatment greatly affect prognosis, and thus, the de-
velopment of new biomarkers has long been awaited. Thus, serum
levels of SeP are expected to put the practical application as a
new biomarker for PAH. PAH is caused by the abnormal prolifer-
ation of cells in the pulmonary arterial walls, resulting in steno-
4
Journal of Cardiology 78 (2021) 1–11
sis/occlusion of the pulmonary microvasculature. Increased pul-
monary artery pressure finally results in right ventricular (RV) fail-
ure and premature death [10,80,81]. Because PAH is a rare dis-
ease and manifests as non-specific symptoms such as shortness of
breath and fatigue, it is difficult for clinicians to make an early di-
agnosis [82]. Thus, the development of specific biomarkers for di-
agnosis is highly desirable. Here, we conducted collaborative re-
search with Alfresa Pharma Co., Ltd. to develop a new technique
based on a sol particle homogeneous immunoassay system for full-
length SeP measurement [75]. Using blood samples from patients
with PAH, we compared serum SeP concentrations between PAH
patients and healthy controls and found that the patient group
had significantly higher levels of SeP [35,75]. Importantly, com-
pared to that for patients with lower serum SeP levels, patients
with higher serum SeP levels showed a worse prognosis based
on total mortality and lung transplantation [75]. Thus, we deter-
mined its potential as a biomarker for prognostic evaluation. Fur-
thermore, we found an interesting correlation between the extent
of changes to serum SeP levels before and after specific treatment
for PAH and the magnitude of changes in major hemodynamic in-
dices including mean pulmonary arterial pressure obtained by car-
diac catheterization [75]. Additionally, the group with increased
serum SeP concentrations during the study had a poorer progno-
sis than the group with decreased serum SeP concentrations. Al-
together, we demonstrated that assessing absolute changes in SeP
during follow-up can provide useful information on the therapeu-
tic effects of multiple combination therapies, prevent excess inva-
sive tests and health care costs, and further enhance prognostic
impacts for PAH patients. Thus, serum SeP levels could be a novel
and useful biomarker in the management of PAH patients (Fig. 6)
[75]. Based on this series of research on SeP, we provided a foun-
dation for the development of new biomarkers for PAH through
translational research from basic studies to clinical application. In
K. Satoh Journal of Cardiology 78 (2021) 1–11

Fig. 4. Mechanism of selenoprotein P expression in patient-derived pulmonary artery vascular smooth muscle cells.
ApoER2, apolipoprotein E receptor 2; ATP, adenosine triphosphate; FoxO3a, forkhead box transcription factor O3a; GCLC, glutamate cysteine ligase catalytic subunit; GCLM,
glutamate cysteine ligase regulatory subunit; GSS, glutathione synthase; HIF-1α , hypoxia-inducible factor 1α ; PAH, pulmonary arterial hypertension; PASMCs, pulmonary
artery vascular smooth muscle cells; ROS, reactive oxygen species; SeP, selenoprotein P. Figure adapted from Kikuchi et al. [18].

Fig. 5. Mechanism underlying the effect of selenoprotein P on vascular smooth muscle cells derived from patients.
ApoER2, apolipoprotein E receptor 2; FoxO3a, forkhead box transcription factor O3a; GSH, glutathione; GSH/GSSG: reduced glutathione/oxidized glutathione ratio; HIF-1α ,
hypoxia inducible factor 1α ; ROS, reactive oxygen species; PAH, pulmonary arterial hypertension; PASMCs, pulmonary artery vascular smooth muscle cells; SeP, selenoprotein
P. Figure adapted from Kikuchi et al. [18].

5
K. Satoh
Fig. 6. Development of a new technique based on a sol particle homogeneous immunoassay (SPIA) system for full-length SeP measurement.
NT, N-terminal; CT, C-terminal; mPAP, mean pulmonary artery pressure; SeP, selenoprotein P. Figure adapted from Kikuchi et al. [75].
the future, it is expected that this research will be further devel-
oped and that a new biomarker for the disease will be put into
practical use. Currently, we are continuously working to improve
the stability of the measurement using the kit. In this way, we have
developed a serum SeP assay reagent through joint research with
Alfresa Pharma for the purpose of early diagnosis to improve PAH
patient prognosis and are preparing for clinical performance tests.
ADAMTS8
In addition to the discovery of SeP, we also found a novel pro-
tein, ADAMTS8 (a disintegrin and metalloproteinase with throm-
bospondin motifs 8), which promotes the development of PAH [19].
ADAMTS8 is specifically expressed in the lung and heart. Analy-
ses of genetically modified animals and clinical samples from pa-
tients with PAH revealed that increased ADAMTS8 promotes the
abnormal proliferation of PAH-PASMCs and RV failure [19]. More
importantly, we revealed a surprising finding that one of the exist-
ing therapeutic agents for infectious diseases, mebendazole, sup-
presses ADAMTS8 and exhibits a remarkable therapeutic effect in
an animal model of severe PAH [19]. Thus, mebendazole, which is
commonly used for the treatment of parasites, is expected to be
useful for the treatment of pulmonary hypertension. In patients
with PAH, the inner lumen of the pulmonary arteries becomes
abnormally narrow due to the thickening of the layer of vascu-
lar cells including PAH-PASMCs that feed blood from the heart to
the lungs, resulting in poor blood flow. In addition, the right ven-
tricle is stressed by the increased pulmonary vascular resistance
through the narrowing of pulmonary arteries, which results in re-
duced RV function and right heart failure [83]. However, it has not
been clarified how we can cure this RV failure [83]. We used many
clinical specimens accumulated at our department and found that
6
Journal of Cardiology 78 (2021) 1–11
ADAMTS8, which had never been suggested to be associated with
PAH, was found to be a novel etiological factor of the disease. As
a result of analysis using an animal model of PAH and many clin-
ical specimens, we revealed for the first time that ADAMTS8 pro-
motes narrowing of the pulmonary vascular lumen and RV failure
(Fig. 7). Furthermore, in that study, we performed drug discovery
screening using PAH-PASMCs. The administration of mebendazole
to an animal model of PAH suppressed the increase in ADAMTS8
and significantly improved pulmonary hypertension. Based on the
results of this research, it is expected that a new drug treatment
for PAH based on mebendazole, which targets ADAMTS8, will be
developed in the future.
Drug discovery for PAH
Based on the progress related to techniques used for drug dis-
covery, we recently conducted an exhaustive search of 5,562 com-
pound libraries at Tohoku University to identify new therapeutic
agents for PAH [31,33,69] (Fig. 8). As a cause of PAH, it is known
that cells of the pulmonary arteries, including PAH-PASMCs, pro-
liferate like cancer cells, and we found that celastramycin strongly
inhibited their proliferation [31]. Furthermore, we found that celas-
tramycin has anti-inflammatory, anti-oxidative stress, and mito-
chondrial function-improving effects and exhibits a remarkable
therapeutic effect in animal models of PAH [31] (Fig. 9). It is ex-
pected that this agent will be applied to the clinical treatment of
PAH, which still has no fundamental remedy. Again, in patients
with PAH, the abnormal proliferation of cells in the pulmonary ar-
terial wall causes stenosis/occlusion of the pulmonary arteries, re-
sulting in high pulmonary artery pressure and an excessive over-
load to the right ventricle [66,67]. Accordingly, this is an incurable
disease that causes right heart failure and death [82,84], which is
often refractory to treatment and eventually requires a lung trans-
K. Satoh Journal of Cardiology 78 (2021) 1–11

Fig. 7. Schematic representation of molecular mechanisms of ADAMTS8-mediated pulmonary vascular remodeling and RV dysfunction.
ADAMTS8, a disintegrin and metalloproteinase with thrombospondin motifs 8; PH, pulmonary hypertension; RV, right ventricular; PAH, pulmonary arterial hypertension;
PASMC, pulmonary artery smooth muscle cell; ECM, extracellular matrix. Figure adapted from Omura et al. [19].

Fig. 8. The schema of the primary culture of pulmonary artery smooth muscle cells from patients with pulmonary arterial hypertension (PAH-PASMCs) and screening of the
Tohoku University Compound Library (5562 compounds).
Schematic outline of high-throughput screening to identify celastramycin, which was found to inhibit PAH-PASMC proliferation with minimal harmful effects. PAH-PASMCs,
pulmonary artery smooth muscle cells harvested from patients with PAH. Figure adapted from Kurosawa et al. [31].

7
K. Satoh Journal of Cardiology 78 (2021) 1–11

Fig. 9. Schematic representation of the molecular mechanisms promoting inflammation, oxidative stress, and mitochondrial dysfunction through activation of hypoxia in-
ducible factor 1α (HIF-1α ) and NF-ĸB in PAH-PASMCs.
Constitutively activated HIF-1α induces the transcription of many genes and the dysregulation of mitochondrial energy metabolism, which promotes cell proliferation,
apoptosis-resistance, survival, and stress resistance by targeting several downstream genes. Celastramycin treatment downregulates HIF-1α and NF-κ B and upregulates Nrf2
in PAH-PASMCs. These effects result in decreased reactive oxygen species (ROS) and inflammation with recovered mitochondrial energy metabolism, leading to the inhibition
of excessive proliferation in PAH-PASMCs. PASMCs, pulmonary artery vascular smooth muscle cells. Figure adapted from Kurosawa et al. [31].

plant [9,66]. In particular, the medications currently used for the
treatment of PAH aim to lower the pulmonary artery pressure by
expanding the blood vessel and reducing vascular resistance [66].
However, a fundamental therapeutic drug that suppresses PAH-
PASMC proliferation itself has not yet been used clinically [1,67].
Therefore, the development of a completely new therapeutic drug
for PAH is desired. Using PAH-PASMCs that show abnormal pro-
liferative properties derived from patients with PAH, we searched
for therapeutic drug candidates using cell growth inhibition as
an index and specifically, a compound that does not affect cells
derived from healthy individuals [31,33,69]. Interestingly, celas-
tramycin strongly increased expression of the downstream Nrf2
protein by suppressing the expression of the protein Keap1, which
responds to oxidative stress, and exhibited an excellent effect of
suppressing oxidative stress (Fig. 8) [31]. Furthermore, we con-
firmed the therapeutic effect of celastramycin in rodent models of
pulmonary hypertension using mice and rats (Fig. 9). Altogether,
we confirmed the efficacy of a completely new therapeutic agent
that targets the abnormal proliferation of PAH-PASMCs (Fig. 10).
During the same process of a comprehensive search of 5,562 com-
pounds, we also found that emetine, the main component of an
emetic agent, has a therapeutic effect on PAH [33]. Indeed, eme-
tine significantly inhibited the proliferation of PAH-PASMCs. Fur-
thermore, we confirmed that it has an anti-inflammatory effect
and an anti-oxidative stress effect, with a remarkable therapeu-
tic impact in animal models of pulmonary hypertension. Interest-
ingly, emetine exhibited excellent oxidative stress-suppressing ef-
fects by downregulating the expression of CyPA and Bsg, which
amplify oxidative stress [16,33,60,69]. Furthermore, the administra-
tion of emetine significantly ameliorated hemodynamics in animal
models of pulmonary hypertension. Based on this research, it is
expected that this drug will lead to the development of new ther-
apeutic agents for PAH.
Right ventricular failure
RV failure is the leading cause of death in pulmonary hyperten-
sion. The pathophysiology of cardiac hypertrophy and heart failure
has a complicated background, which remains unclear [51,85,86].
Although therapeutic agents for PAH have been explored, devel-
oped, and clinically applied with a focus on pulmonary vasodila-
tion, there are still many lives that cannot be saved due to the
progression of RV failure [83]. To improve prognosis for patients
with PAH, it is necessary to develop a drug to treat RV failure
[87]. However, as compared to those of left ventricular failure, the
molecular mechanisms of RV failure are poorly understood. Thus,
it is necessary to elucidate the mechanisms underlying the func-
tional maintenance and hypertrophy/fibrosis of the right ventricle,
which structurally is completely different from the left ventricle
[88]. It is generally considered that the right ventricle is vulner-
able to pressure overload as compared to the left ventricle. Here,
we elucidated the genes that are specifically induced by pressure
overload in the right and left ventricle [42], which have never been
clarified. To induce pressure overload in respective ventricles, we
performed pulmonary artery constriction or transverse aortic con-
striction in mice. Finally, we demonstrated that oxidative stress
and Rho-kinase activation promote cardiac hypertrophy and heart
failure. We assumed that it would be important to apply these ba-
sic research results to clinical applications, such as drug discovery
[42,89–93]. Here, we finally found that celastrol is useful for the
treatment of heart failure and post-capillary pulmonary hyperten-
sion [30].
Outlook
Early diagnosis of PAH is difficult because there is no biomarker.
Therefore, it is expected that prognosis will be improved through
the development of an early diagnostic technique and therapeutic

8
K. Satoh Journal of Cardiology 78 (2021) 1–11

Fig. 10. Schematic representation of the molecular mechanisms of celastramycin-mediated effects on PAH-PASMCs.
Abnormally activated hypoxia-inducible factor-1α (HIF-1α ) and nuclear factor-κ B (NF-ĸB) promote inflammation, oxidative stress, and mitochondrial dysfunction, which
induce excessive proliferation of PAH-PASMCs. Activation of NF-ĸB also increases the production of cytokines/chemokines and growth factors, which recruit abundant in-
flammatory cells, leading to the additional production of growth factors. Secreted growth factors activate NADPH oxidases (NOX), one of the main sources of intracellular
ROS, and induce the production of cytosolic reactive oxygen species (ROS) in PAH-PASMCs. Here, celastramycin directly binds zinc finger C3H1 domain-containing protein
(ZFC3H1), a zinc finger protein, which downregulates the expression of bromodomain-containing protein 4 (BRD4) and HIF-1α . Celastramycin-mediated decreases in BRD4
downregulate NF-ĸB and Kelch-like ECH-associated protein 1 (Keap1), which suppress inflammation and activate NF-E2-related factor 2 (Nrf2), leading to the upregulation
of antioxidants, such as NAD(P)H quinone dehydrogenase-1 (NQO1), superoxide dismutase 2 (SOD2), heme oxygenase-1 (HMOX1), and glutamate-cysteine ligase catalytic
subunit (GCLC), resulting in the inhibition of ROS production. Constitutively activated HIF-1α in PAH-PASMCs upregulates dynamin-1-like protein (DRP1) and promotes mi-
tochondrial fission and induces the dysregulation of mitochondrial energy metabolism, leading to less oxidative phosphorylation (OXPHOS) with metabolic abnormalities.
Mitochondrial ROS (mROS) promotes the phosphorylation of AMP-activated protein kinase (AMPK), which induces peroxisome proliferator-activated receptor γ coactivator
1-α (PGC-1α ) to promote mitochondrial biogenesis, whereas mROS is downregulated because of mitochondrial metabolic abnormalities in PAH-PASMCs. These mitochondrial
abnormalities are reversed by ZFC3H1-mediated HIF-1α downregulation. Altogether, celastramycin inhibits the abnormal proliferation of PAH-PASCMs through changes in
these transcription factors.
PASMCs, pulmonary artery vascular smooth muscle cells. Figure adapted from Kurosawa et al. [31].

agents focusing on pathogenic proteins. As described in this pa-
per, we identified several pathogenic proteins for PAH and are now
proceeding with drug discovery and biomarker development. For
diseases other than PAH, we used the same method to discover
pathogenic proteins for chronic thromboembolic pulmonary hyper-
tension and dissecting aortic aneurysms [13–15,17,29,32,94–102].
In this way, by applying the rapid progress of cutting-edge sci-
ence and technology for clinical applications, we are conducting re-
search to bring more effective and safer medical treatments to pa-
tients with cardiovascular diseases. With the goal of making vari-
ous intractable diseases easily treatable by oral medication, we aim
to elucidate the essential etiology and develop therapeutic drugs
for cardiovascular diseases [48].
Acknowledgment
Part of the author’s research described in this paper was carried
out with the support of the National Research and Development
Agency, Japan Agency for Medical Research and Development for
practical application of intractable diseases and the Japan Society
for the Promotion of Science Grant-in-Aid for Scientific Research. I
would also like to thank the many collaborators of the Drug Dis-
covery Agency, Tohoku University Graduate School of Medicine and
Graduate School of Pharmaceutical Sciences.
References
[1] Sato H, Sugimura K, Miura M, Konno R, Kozu K, Yaoita N, et al. Beneficial
effects of imatinib in a patient with suspected pulmonary veno-occlusive dis-
ease. Tohoku J Exp Med 2019;247:69–73.
[2] Satoh K, Kikuchi N, Kurosawa R, Shimokawa H. PDE1C negatively regulates
growth factor receptor degradation and promotes VSMC proliferation. Circ Res
2015;116:1098–100.
[3] Dai Z, Fukumoto Y, Tatebe S, Sugimura K, Miura Y, Nochioka K, et al. OCT
imaging for the management of pulmonary hypertension. JACC Cardiovasc
Imaging 2014;7:843–5.
[4] Miura Y, Fukumoto Y, Sugimura K, Oikawa M, Nakano M, Tatebe S, et al. Iden-
tification of new prognostic factors of pulmonary hypertension. Circ J
2010;74:1965–71.
[5] Satoh K, Fukumoto Y, Nakano M, Sugimura K, Nawata J, Demachi J,
et al. Statin ameliorates hypoxia-induced pulmonary hypertension asso-
ciated with down-regulated stromal cell-derived factor-1. Cardiovasc Res
2009;81:226–34.
[6] Rabieyousefi M, Soroosh P, Satoh K, Date F, Ishii N, Yamashita M, et al. In-
dispensable roles of OX40L-derived signal and epistatic genetic effect in im-
mune-mediated pathogenesis of spontaneous pulmonary hypertension. BMC
Immunol 2011;12:67.
[7] Tatebe S, Fukumoto Y, Sugimura K, Miyamichi-Yamamoto S, Aoki T, Miura Y,
et al. Clinical significance of reactive post-capillary pulmonary hypertension
in patients with left heart disease. Circ J 2012;76:1235–44.
[8] Shimizu T, Fukumoto Y, Tanaka S, Satoh K, Ikeda S, Shimokawa H. Crucial role
of ROCK2 in vascular smooth muscle cells for hypoxia-induced pulmonary
hypertension in mice. Arterioscler Thromb Vasc Biol 2013;33:2780–91.
[9] Elias-Al-Mamun M, Satoh K, Tanaka S, Shimizu T, Nergui S, Miy-
ata S, et al. Combination therapy with fasudil and sildenafil ameliorates
monocrotaline-induced pulmonary hypertension and survival in rats. Circ J
2014;78:967–76.
[10] Tatebe S, Fukumoto Y, Oikawa-Wakayama M, Sugimura K, Satoh K, Miura Y,
et al. Enhanced [18 F]fluorodeoxyglucose accumulation in the right ventricu-
lar free wall predicts long-term prognosis of patients with pulmonary hyper-
tension: a preliminary observational study. Eur Heart J Cardiovasc Imaging
2014;15:666–72.
[11] Omura J, Satoh K, Kikuchi N, Satoh T, Kurosawa R, Nogi M, et al. Protective
roles of endothelial AMP-activated protein kinase against hypoxia-induced
pulmonary hypertension in mice. Circ Res 2016;119:197–209.
[12] Yaoita N, Satoh K, Shimokawa H. Novel therapeutic targets of pulmonary hy-
pertension. Arterioscler Thromb Vasc Biol 2016;36:e97–102.

9
K. Satoh
[13] Akizuki M, Sugimura K, Aoki T, Kakihana T, Tatebe S, Yamamoto S, et al. Use-
fulness of ventilatory gas analysis for the non-invasive evaluation of the
severity of chronic thromboembolic pulmonary hypertension. Int J Cardiol
2019;296:149–54.
[14] Akizuki M, Sugimura K, Aoki T, Kakihana T, Tatebe S, Yamamoto S,
et al. Non-invasive screening using ventilatory gas analysis to distinguish be-
tween chronic thromboembolic pulmonary hypertension and pulmonary ar-
terial hypertension. Respirology 2020;25:427–34.
[15] Kozu K, Satoh K, Aoki T, Tatebe S, Miura M, Yamamoto S, et al. Cyclophilin
A as a biomarker for the therapeutic effect of balloon angioplasty in chronic
thromboembolic pulmonary hypertension. J Cardiol 2020;75:415–23.
[16] Satoh K, Satoh T, Kikuchi N, Omura J, Kurosawa R, Suzuki K, et al. Basigin
mediates pulmonary hypertension by promoting inflammation and vascular
smooth muscle cell proliferation. Circ Res 2014;115:738–50.
[17] Satoh T, Satoh K, Yaoita N, Kikuchi N, Omura J, Kurosawa R, et al. Activated
TAFI promotes the development of chronic thromboembolic pulmonary hy-
pertension: a possible novel therapeutic target. Circ Res 2017;120:1246–62.
[18] Kikuchi N, Satoh K, Kurosawa R, Yaoita N, Elias-Al-Mamun M, Siddique MAH,
et al. Selenoprotein P promotes the development of pulmonary arterial hy-
pertension. Circulation 2018;138:600–23.
[19] Omura J, Satoh K, Kikuchi N, Satoh T, Kurosawa R, Nogi M, et al. ADAMTS8
promotes the development of pulmonary arterial hypertension and
right ventricular failure: a possible novel therapeutic target. Circ Res
2019;125:884–906.
[20] Satoh K, Kagaya Y, Nakano M, Ito Y, Ohta J, Tada H, et al. Important role
of endogenous erythropoietin system in recruitment of endothelial progen-
itor cells in hypoxia-induced pulmonary hypertension in mice. Circulation
2006;113:1442–50.
[21] Tada H, Kagaya Y, Takeda M, Ohta J, Asaumi Y, Satoh K, et al. Endogenous
erythropoietin system in non-hematopoietic lineage cells plays a protective
role in myocardial ischemia/reperfusion. Cardiovasc Res 2006;71:466–77.
[22] Nakano M, Satoh K, Fukumoto Y, Ito Y, Kagaya Y, Ishii N, et al. Important role
of erythropoietin receptor to promote VEGF expression and angiogenesis in
peripheral ischemia in mice. Circ Res 20 07;10 0:662–9.
[23] Satoh K, Fukumoto Y, Nakano M, Kagaya Y, Shimokawa H. Emergence of the
erythropoietin/erythropoietin receptor system as a novel cardiovascular ther-
apeutic target. J Cardiovasc Pharmacol 2011;58:570–4.
[24] Kagaya Y, Asaumi Y, Wang W, Takeda M, Nakano M, Satoh K, et al. Cur-
rent perspectives on protective roles of erythropoietin in cardiovascular sys-
tem: erythropoietin receptor as a novel therapeutic target. Tohoku J Exp Med
2012;227:83–91.
[25] Satoh K. Globotriaosylceramide induces endothelial dysfunction in Fabry dis-
ease. Arterioscler Thromb Vasc Biol 2014;34:2–4.
[26] Kina-Tanada M, Sakanashi M, Tanimoto A, Kaname T, Matsuzaki T, Noguchi K,
et al. Long-term dietary nitrite and nitrate deficiency causes the metabolic
syndrome, endothelial dysfunction and cardiovascular death in mice. Dia-
betologia 2017;60:1138–51.
[27] Abe Y, Ito K, Hao K, Shindo T, Ogata T, Kagaya Y, et al. Extracorporeal low-en-
ergy shock-wave therapy exerts anti-inflammatory effects in a rat model of
acute myocardial infarction. Circ J 2014;78:2915–25.
[28] Ohtsuki T, Satoh K, Omura J, Kikuchi N, Satoh T, Kurosawa R, et al. Prognostic
impacts of plasma levels of cyclophilin A in patients with coronary artery
disease. Arterioscler Thromb Vasc Biol 2017;37:685–93.
[29] Yaoita N, Satoh K, Satoh T, Sugimura K, Tatebe S, Yamamoto S, et al. Throm-
bin-activatable fibrinolysis inhibitor in chronic thromboembolic pulmonary
hypertension. Arterioscler Thromb Vasc Biol 2016;36:1293–301.
[30] Sunamura S, Satoh K, Kurosawa R, Ohtsuki T, Kikuchi N, Elias-Al-Mamun Md,
et al. Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction
and postcapillary pulmonary hypertension in mice. Proc Natl Acad Sci USA
2018;115:E7129–38.
[31] Kurosawa R, Satoh K, Kikuchi N, Kikuchi H, Saigusa D, Elias-Al-Mamun Md,
et al. Identification of celastramycin as a novel therapeutic agent for pul-
monary arterial hypertension. Circ Res 2019;125:309–27.
[32] Nogi M, Satoh K, Sunamura S, Kikuchi N, Satoh T, Kurosawa R, et al. Small
GTP-binding protein GDP dissociation stimulator prevents thoracic aortic
aneurysm formation and rupture by phenotypic preservation of aortic smooth
muscle cells. Circulation 2018;138:2413–33.
[33] Siddique MAH, Satoh K, Kurosawa R, Kikuchi N, Elias-Al-Mamun M, Omura J,
et al. Identification of emetine as a therapeutic agent for pulmonary arte-
rial hypertension: novel effects of an old drug. Arterioscler Thromb Vasc Biol
2019;39:2367–85.
[34] Satoh K, Kikuchi N, Satoh T, Kurosawa R, Sunamura S, Siddique MAH,
et al. Identification of novel therapeutic targets for pulmonary arterial hy-
pertension. Int J Mol Sci 2018;19:4081.
[35] Kikuchi N, Satoh K, Saito Y, Shimokawa H. Response by Kikuchi et al. regard-
ing article, "Selenoprotein P promotes the development of pulmonary arte-
rial hypertension: a possible novel therapeutic target. Circulation 2019;139:
724–725.
[36] Stenmark KR, Fagan KA, Frid MG. Hypoxia-induced pulmonary vascular re-
modeling: cellular and molecular mechanisms. Circ Res 2006;99:675–91.
[37] Voelkel NF, Mizuno S, Bogaard HJ. The role of hypoxia in pulmonary
vascular diseases: a perspective. Am J Physiol Lung Cell Mol Physiol
2013;304:L457–65.
[38] Satoh K. AMPKα 2 regulates hypoxia-inducible factor-1α stability and neu-
trophil survival to promote vascular repair after ischemia. Circ Res
2017;120:8–10.
10
Journal of Cardiology 78 (2021) 1–11
[39] Dromparis P, Paulin R, Sutendra G, Qi AC, Bonnet S, Michelakis ED. Uncou-
pling protein 2 deficiency mimics the effects of hypoxia and endoplasmic
reticulum stress on mitochondria and triggers pseudohypoxic pulmonary vas-
cular remodeling and pulmonary hypertension. Circ Res 2013;113:126–36.
[40] Boucherat O, Vitry G, Trinh I, Paulin R, Provencher S, Bonnet S. The cancer
theory of pulmonary arterial hypertension. Pulm Circ 2017;7:285–99.
[41] Mohlin S, Wigerup C, Jogi A, Pahlman S. Hypoxia, pseudohypoxia and cellular
differentiation. Exp Cell Res 2017;356:192–6.
[42] Ikeda S, Satoh K, Kikuchi N, Miyata S, Suzuki K, Omura J, et al. Crucial role
of Rho-kinase in pressure overload-induced right ventricular hypertrophy and
dysfunction in mice. Arterioscler Thromb Vasc Biol 2014;34:1260–71.
[43] Nakano M, Fukumoto Y, Satoh K, Ito Y, Kagaya Y, Ishii N, et al. OX40 ligand
plays an important role in the development of atherosclerosis through vasa
vasorum neovascularization. Cardiovasc Res 2010;88:539–46.
[44] Ohtsuki T, Satoh K, Shimizu T, Ikeda S, Kikuchi N, Satoh T, et al. Identification
of adipsin as a novel prognostic biomarker in patients with coronary artery
disease. J Am Heart Assoc 2019;8:e013716.
[45] Satoh K, Matoba T, Suzuki J, O’Dell MR, Nigro P, Cui Z, et al. Cyclophilin A me-
diates vascular remodeling by promoting inflammation and vascular smooth
muscle cell proliferation. Circulation 2008;117:3088–98.
[46] Satoh K, Nigro P, Matoba T, O’Dell MR, Cui Z, Shi X, et al. Cyclophilin A en-
hances vascular oxidative stress and the development of angiotensin II-in-
duced aortic aneurysms. Nat Med 2009;15:649–56.
[47] Satoh K, Nigro P, Berk BC. Oxidative stress and vascular smooth muscle
cell growth: a mechanistic linkage by cyclophilin A. Antioxid Redox Signal
2010;12:675–82.
[48] Satoh K. Cyclophilin A in cardiovascular homeostasis and diseases. Tohoku J
Exp Med 2015;235:1–15.
[49] Satoh K, Godo S, Saito H, Enkhjargal B, Shimokawa H. Dual roles of vascu-
lar-derived reactive oxygen species: with a special reference to hydrogen per-
oxide and cyclophilin A. J Mol Cell Cardiol 2014;73:50–6.
[50] Nigro P, Satoh K, O’Dell MR, Soe NN, Cui Z, Mohan A, et al. Cyclophilin A
is an inflammatory mediator that promotes atherosclerosis in apolipoprotein
E-deficient mice. J Exp Med 2011;208:53–66.
[51] Satoh K, Nigro P, Zeidan A, Soe NN, Jaffre F, Oikawa M, et al. Cyclophilin A
promotes cardiac hypertrophy in apolipoprotein E-deficient mice. Arterioscler
Thromb Vasc Biol 2011;31:1116–23.
[52] Miller LH, Ackerman HC, Su XZ, Wellems TE. Malaria biology and disease
pathogenesis: insights for new treatments. Nat Med 2013;19:156–67.
[53] Satoh K, Berk BC, Shimokawa H. Vascular-derived reactive oxygen species for
homeostasis and diseases. Nitric Oxide 2011;25:211–15.
[54] Shimokawa H, Satoh K. Light and dark of reactive oxygen species for vascular
function. J Cardiovasc Pharmacol 2015;65:412–18.
[55] Shimokawa H, Satoh K. Vascular function. Arterioscler Thromb Vasc Biol
2014;34:2359–62.
[56] Guo H, Majmudar G, Jensen TC, Biswas C, Toole BP, Gordon MK. Characteriza-
tion of the gene for human EMMPRIN, a tumor cell surface inducer of matrix
metalloproteinases. Gene 1998;220:99–108.
[57] Nabeshima K, Iwasaki H, Nishio J, Koga K, Shishime M, Kikuchi M. Expres-
sion of emmprin and matrix metalloproteinases (MMPs) in peripheral nerve
sheath tumors: emmprin and membrane-type (MT)1-MMP expressions are
associated with malignant potential. Anticancer Res 2006;26:1359–67.
[58] Yan L, Zucker S, Toole BP. Roles of the multifunctional glycoprotein, EMMPRIN
(basigin; CD147), in tumour progression. Thromb Haemost 2005;93:199–204.
[59] Seizer P, Schonberger T, Schott M, Lang MR, Langer HF, Bigalke B, et al. EMM-
PRIN and its ligand cyclophilin A regulate MT1-MMP, MMP-9 and M-CSF dur-
ing foam cell formation. Atherosclerosis 2010;209:51–7.
[60] Suzuki K, Satoh K, Ikeda S, Sunamura S, Otsuki T, Satoh T, et al. Basigin pro-
motes cardiac fibrosis and failure in response to chronic pressure overload in
mice. Arterioscler Thromb Vasc Biol 2016;36:636–46.
[61] Curtin KD, Meinertzhagen IA, Wyman RJ. Basigin (EMMPRIN/CD147) interacts
with integrin to affect cellular architecture. J Cell Sci 2005;118:2649–60.
[62] Siwik DA, Kuster GM, Brahmbhatt JV, Zaidi Z, Malik J, Ooi H, et al. EMMPRIN
mediates beta-adrenergic receptor-stimulated matrix metalloproteinase activ-
ity in cardiac myocytes. J Mol Cell Cardiol 2008;44:210–17.
[63] Venkatesan B, Valente AJ, Prabhu SD, Shanmugam P, Delafontaine P,
Chandrasekar B. EMMPRIN activates multiple transcription factors in car-
diomyocytes, and induces interleukin-18 expression via Rac1-dependent
PI3K/Akt/IKK/NF-kappaB andMKK7/JNK/AP-1 signaling. J Mol Cell Cardiol
2010;49:655–63.
[64] Seizer P, Geisler T, Bigalke B, Schneider M, Klingel K, Kandolf R, et al. EMM-
PRIN and its ligand cyclophilin A as novel diagnostic markers in inflammatory
cardiomyopathy. Int J Cardiol 2013;163:299–304.
[65] Soe NN, Sowden M, Baskaran P, Kim Y, Nigro P, Smolock EM, et al. Acetyla-
tion of cyclophilin A is required for its secretion and vascular cell activation.
Cardiovasc Res 2014;101:444–53.
[66] Burks M, Stickel S, Galie N. Pulmonary arterial hypertension: combination
therapy in practice. Am J Cardiovasc Drugs 2018;18:249–57.
[67] Bourgeois A, Omura J, Habbout K, Bonnet S, Boucherat O. Pulmonary arte-
rial hypertension: new pathophysiological insights and emerging therapeutic
targets. Int J Biochem Cell Biol 2018;104:9–13.
[68] Satoh K, Kikuchi N, Kurosawa R, Shimokawa H. Checkpoint kinase 1 promotes
the development of pulmonary arterial hypertension. Arterioscler Thromb
Vasc Biol 2019;39:1504–6.
[69] Satoh K. Development of novel therapies for cardiovascular diseases by clini-
cal application of basic research. Circ J 2017;81:1557–63.
K. Satoh
[70] Saito Y, Hayashi T, Tanaka A, Watanabe Y, Suzuki M, Saito E, et al. Selenopro-
tein P in human plasma as an extracellular phospholipid hydroperoxide glu-
tathione peroxidase. Isolation and enzymatic characterization of human se-
lenoprotein P. J Biol Chem 1999;274:2866–71.
[71] Saito Y, Takahashi K. Characterization of selenoprotein P as a selenium supply
protein. Eur J Biochem 2002;269:5746–51.
[72] Misu H, Takamura T, Takayama H, Hayashi H, Matsuzawa-Nagata N, Kurita S,
et al. A liver-derived secretory protein, selenoprotein P, causes insulin resis-
tance. Cell Metab 2010;12:483–95.
[73] Strauss E, Oszkinis G, Staniszewski R. SEPP1 gene variants and abdominal aor-
tic aneurysm: gene association in relation to metabolic risk factors and pe-
ripheral arterial disease coexistence. Sci Rep 2014;4:7061.
[74] Strauss E, Tomczak J, Staniszewski R, Oszkinis G. Associations and interactions
between variants in selenoprotein genes, selenoprotein levels and the devel-
opment of abdominal aortic aneurysm, peripheral arterial disease, and heart
failure. PLoS One 2018;13:e0203350.
[75] Kikuchi N, Satoh K, Satoh T, Yaoita N, Siddique MAH, Omura J, et al. Di-
agnostic and prognostic significance of serum levels of SeP (Selenoprotein
P) in patients with pulmonary hypertension. Arterioscler Thromb Vasc Biol
2019;39:2553–62.
[76] Leopold JA, Loscalzo J. Oxidative enzymopathies and vascular disease. Arte-
rioscler Thromb Vasc Biol 2005;25:1332–40.
[77] Fisslthaler B, Fleming I. Activation and signaling by the AMP-activated protein
kinase in endothelial cells. Circ Res 2009;105:114–27.
[78] Suzuki N, Yamamoto M. Roles of renal erythropoietin-producing (REP)
cells in the maintenance of systemic oxygen homeostasis. Pflugers Arch
2016;468:3–12.
[79] Jardim C, Souza R. Biomarkers and prognostic indicators in pulmonary arterial
hypertension. Curr Hypertens Rep 2015;17:556.
[80] Miyamichi-Yamamoto S, Fukumoto Y, Sugimura K, Ishii T, Satoh K, Miura Y,
et al. Intensive immunosuppressive therapy improves pulmonary hemody-
namics and long-term prognosis in patients with pulmonary arterial hyper-
tension associated with connective tissue disease. Circ J 2011;75:2668–74.
[81] Sato H, Ota H, Sugimura K, Aoki T, Tatebe S, Miura M, et al. Balloon pul-
monary angioplasty improves biventricular functions and pulmonary flow in
chronic thromboembolic pulmonary hypertension. Circ J 2016;80:1470–7.
[82] Lau EMT, Giannoulatou E, Celermajer DS, Humbert M. Epidemiology
and treatment of pulmonary arterial hypertension. Nat Rev Cardiol
2017;14:603–14.
[83] Ryan JJ, Archer SL. The right ventricle in pulmonary arterial hypertension:
disorders of metabolism, angiogenesis and adrenergic signaling in right ven-
tricular failure. Circ Res 2014;115:176–88.
[84] Zamanian RT, Kudelko KT, Sung YK, de Jesus Perez V, Liu J, Spiekerkoet-
ter E. Current clinical management of pulmonary arterial hypertension. Circ
Res 2014;115:131–47.
[85] Kudo S, Satoh K, Nogi M, Suzuki K, Sunamura S, Omura J, et al. SmgGDS as
a crucial mediator of the inhibitory effects of statins on cardiac hypertrophy
and fibrosis: novel mechanism of the pleiotropic effects of statins. Hyperten-
sion 2016;67:878–89.
[86] Minami T, Satoh K, Nogi M, Kudo S, Miyata S, Tanaka S, et al. Statins up-reg-
ulate SmgGDS through β 1-integrin/Akt1 pathway in endothelial cells. Cardio-
vasc Res 2016;109:151–61.
11
Journal of Cardiology 78 (2021) 1–11
[87] Groeneveldt JA, de Man FS, Westerhof BE. The right treatment for the right
ventricle. Curr Opin Pulm Med 2019;25:410–17.
[88] Tuder RM. How do we measure pathology in PAH (lung and RV) and what
does it tell us about the disease. Drug Discov Today 2014;19:1257–63.
[89] Doe Z, Fukumoto Y, Sugimura K, Miura Y, Tatebe S, Yamamoto S, et al. Rho-k-
inase activation in patients with heart failure. Circ J 2013;77:2542–50.
[90] Satoh K, Fukumoto Y, Shimokawa H. Rho-kinase: important new thera-
peutic target in cardiovascular diseases. Am J Physiol Heart Circ Physiol
2011;301:H287–96.
[91] Ellawindy A, Satoh K, Sunamura S, Kikuchi N, Suzuki K, Minami T,
et al. Rho-kinase inhibition during early cardiac development causes arrhyth-
mogenic right ventricular cardiomyopathy in mice. Arterioscler Thromb Vasc
Biol 2015;35:2172–84.
[92] Shimokawa H, Satoh K. 2015 ATVB plenary lecture: Translational research
on Rho-kinase in cardiovascular medicine. Arterioscler Thromb Vasc Biol
2015;35:1756–69.
[93] Shimokawa H, Sunamura S, Satoh K. RhoA/Rho-kinase in the cardiovascular
system. Circ Res 2016;118:352–66.
[94] Yaoita N, Shirakawa R, Fukumoto Y, Sugimura K, Miyata S, Miura Y,
et al. Platelets are highly activated in patients of chronic thromboembolic pul-
monary hypertension. Arterioscler Thromb Vasc Biol 2014;34:2486–94.
[95] Tatebe S, Sugimura K, Aoki T, Miura M, Nochioka K, Yaoita N, et al. Multiple
beneficial effects of balloon pulmonary angioplasty in patients with chronic
thromboembolic pulmonary hypertension. Circ J 2016;80:980–8.
[96] Tatebe S, Fukumoto Y, Sugimura K, Miura Y, Nochioka K, Aoki T, et al. Op-
tical coherence tomography is superior to intravascular ultrasound for diag-
nosis of distal-type chronic thromboembolic pulmonary hypertension. Circ J
2013;77:1081–3.
[97] Sugimura K, Fukumoto Y, Miura Y, Nochioka K, Miura M, Tatebe S,
et al. Three-dimensional-optical coherence tomography imaging of chronic
thromboembolic pulmonary hypertension. Eur Heart J 2013;34:2121.
[98] Tatebe S, Fukumoto Y, Sugimura K, Nakano M, Miyamichi S, Satoh K,
et al. Optical coherence tomography as a novel diagnostic tool for distal type
chronic thromboembolic pulmonary hypertension. Circ J 2010;74:1742–4.
[99] Aoki T, Sugimura K, Nochioka K, Miura M, Tatebe S, Yamamoto S, et al. Effects
of balloon pulmonary angioplasty on oxygenation in patients with chronic
thromboembolic pulmonary hypertension – importance of intrapulmonary
shunt. Circ J 2016;80:2227–34.
[100] Takahashi K, Matsumoto Y, Doe Z, Kanazawa M, Satoh K, Shimizu T,
et al. Combination therapy with atorvastatin and amlodipine suppresses an-
giotensin II-induced aortic aneurysm formation. PLoS One 2013;8:e72558.
[101] Yaoita N, Satoh K, Satoh T, Shimizu T, Saito S, et al. Identification of the novel
variants in patients with chronic thromboembolic pulmonary hypertension. J
Am Heart Assoc 2020:e015902.
[102] Kurosawa R, Satoh K, Nakata T, Shindo T, Kikuchi N, Satoh T, et al. Identifica-
tion of celastrol as a novel therapeutic agent for pulmonary arterial hyperten-
sion and right ventricular failure through suppression of basigin/cyclophilin
A. Arterioscler Thromb Vasc Biol 2021:ATVBAHA120315731. In press. doi:10.
1161/ATVBAHA.120.315731.