Am J Cardiovasc Drugs (2015) 15:225–234

DOI 10.1007/s40256-015-0125-4

LEADING ARTICLE

Novel Targets of Drug Treatment for Pulmonary Hypertension

Jian Hu1 • Qinzi Xu1 • Charles McTiernan1 • Yen-Chun Lai1 •

David Osei-Hwedieh1 • Mark Gladwin1,2

Published online: 28 May 2015

Ó Springer International Publishing Switzerland 2015

Abstract Biomedical advances over the last decade have
identified the central role of proliferative pulmonary arterial
smooth muscle cells (PASMCs) in the development of pul-
monary hypertension (PH). Furthermore, promoters of pro-
liferation and apoptosis resistance in PASMCs and endothelial
cells, such as aberrant signal pathways involving growth
factors, G protein-coupled receptors, kinases, and mi-
croRNAs, have also been described. As a result of these dis-
coveries, PH is currently divided into subgroups based on the
underlying pathology, which allows focused and targeted
treatment of the condition. The defining features of PH, which
subsequently lead to vascular wall remodeling, are dys-
regulated proliferation of PASMCs, local inflammation, and
apoptosis-resistant endothelial cells. Efforts to assess the
relative contributions of these factors have generated several
promising targets. This review discusses recent novel targets
of therapies for PH that have been developed as a result of
these advances, which are now in pre-clinical and clinical
trials (e.g., imatinib [phase III]; nilotinib, AT-877ER, ritux-
imab, tacrolimus, paroxetine, sertraline, fluoxetine, bardox-
olone methyl [phase II]; and sorafenib, FK506, aviptadil,
endothelial progenitor cells (EPCs) [phase I]). While sub-
stantial progress has been made in recent years in targeting key
molecular pathways, PH still remains without a cure, and these
novel therapies provide an important conceptual framework
& Jian Hu
jih67@pitt.edu
1 peripheral edema, syncope, right heart failure, and death [1,
Pittsburgh Heart, Lung, Blood and Vascular Medicine
Institute, University of Pittsburgh, E1226 BST 200 Lothrop
Street, Pittsburgh, PA 15213, USA
2
Division of Pulmonary, Allergy and Critical Care Medicine,
University of Pittsburgh, Pittsburgh, USA
of categorizing patients on the basis of molecular pheno-
type(s) for effective treatment of the disease.
Key Points
Several novel strategies have emerged for pulmonary
hypertension in recent years.
Pre-clinical and clinical trials have been performed
to evaluate the novel strategies.
The following drugs, acting on novel targets, are
currently being evaluated in clinical trials: imatinib
(phase III); nilotinib, AT-877ER, rituximab,
tacrolimus, paroxetine, sertraline, fluoxetine,
bardoxolone methyl (phase II); and sorafenib,
FK506, aviptadil, endothelial progenitor cells (EPCs)
(phase I).
1 Introduction
Pulmonary hypertension (PH) is a progressive vascular dis-
ease caused by vasoconstriction and structural remodeling of
arterioles that result in the reduction of vessel elasticity and
inner diameter. These changes increase the resting mean
pulmonary arterial pressure (PAP) (C25 mmHg) and can
lead to dyspnea, fatigue, cough, chest pain, palpitations,
2]. In the US population, the age-standardized mortality rate
for PH has significantly increased from 5.5 per 100,000
population in 2001 to 6.5 per 100,000 in 2010. In 2010,
women showed significantly higher mortality rates than
226
men, and non-Hispanic blacks showed significantly higher
mortality rates than non-Hispanic whites. Aged population
cohorts (75–84 and C85 years of age) show the highest PH
mortality (47.9/100,000 and 108.7/100,000, respectively,
2010 data) [3]. Mechanisms for the development of PH are
complex and may be idiopathic, genetic, or secondary to left
heart disease, lung diseases, and/or chronic thromboem-
bolism. Five subgroups of PH have been defined on the basis
of the etiology [1], and current research progress on the novel
therapeutic targets is focused on group 1 PH [pulmonary
arterial hypertension (PAH)].
PAH is characterized by a progressive increase in pul-
monary vascular resistance (PVR) caused by pulmonary
artery remodeling and vaso-occlusion. The most important
mechanism for PAH development is endothelial dysfunction
and/or injury, which leads to imbalanced production of en-
dogenous vasodilators, such as prostacyclin and nitric oxide,
and vasoconstrictors, such as endothelin and serotonin.
Without treatment, the survival rates of PAH at 1 year, 3, and
5 years are 68, 48, and 34 %, respectively [4]. Contemporary
drugs used to treat PAH target three pathways: the cyclic
guanosine monophosphate signaling pathway (e.g., sildenafil
and tadalafil), prostacyclin signaling pathway (e.g., epopros-
tenol and iloprost), and endothelin signaling pathway (e.g.,
bosentan and ambrisentan). More recently, new drugs tar-
geting these major pathways (e.g., riociguat, selexipag, and
macitentan) have been shown to be effective in the treatment
of PAH and have been approved by US Food and Drug
Administration (FDA). Although current treatments appear to
relieve symptoms, improve exercise capacity, and prevent
hospitalizations, only limited evidence for disease reversal
has been observed. In recent years, several novel strategies
have emerged for PH treatment, and this article focuses on
new and promising therapeutic approaches.
2 Novel Targets of Drug Treatment
2.1 Receptor Tyrosine Kinase Inhibitors
Receptor tyrosine kinases (RTKs) are a class of high-affi-
nity cell surface receptors for a variety of growth factors,
hormones, and cytokine ligands. Platelet-derived growth
factor (PDGF), epidermal growth factor (EGF), fibroblast
growth factor (FGF), and c-kit-receptors play pathogenic
roles in the development of PH [5, 6], as these RTK ligands
increase proliferation and migration of smooth muscle cells
(SMCs) and endothelial cells (ECs) in lungs.
Several tyrosine kinase inhibitors (TKIs) are currently
under development. Imatinib (GleevecÒ) inhibits PDGF,
c-kit, and c-Abl receptors. The use of imatinib has been
shown to inhibit proliferation and migration of pulmonary
arterial smooth muscle cells (PASMCs) in rodents and
J. Hu et al.
humans, and to exert pro-apoptotic effects in isolated
PASMCs [7, 8]. Imatinib has also been reported to prevent
right ventricular and pulmonary vascular remodeling and to
improve pulmonary hemodynamics in animal models [5,
9]. After several reported cases of improved exercise ca-
pacity and hemodynamics of PH patients given imatinib
treatment [10–14], the compound was evaluated for safety,
tolerability, and efficacy in 59 PH patients in a double-
blinded, placebo-controlled multicenter, phase II trial [15].
This clinical trial has shown that imatinib decreases PVR
and increases cardiac output, but has no significant im-
provement in the 6-min walk distance (6MWD). However,
subgroup analysis revealed that patients with severely im-
proved PVR showed a significant increase in 6MWD and
hemodynamics after receiving imatinib. In a phase III trial
of 202 patients with severe PH, patients receiving imatinib
showed a significant improvement in 6MWD, decreased
mean PAP and PVR, and increased cardiac output [16].
Nilotinib is another TKI that shows greater potency and
selectivity in inhibition of the BCR-ABL tyrosine kinase than
does imatinib. Nilotinib has been demonstrated to prevent an-
gioproliferation in a rodent model of PH with systemic sclerosis
[17]. However, a phase II clinical trial conducted in 23 patients
was terminated because of serious adverse effects including
cardiopulmonary disorders (e.g., pulseless electrical activity,
right ventricular dysfunction, acute respiratory failure, and
PAH worsening) and hepatobiliary disorders [e.g., cholecystitis
and cholelithiasis (NCT01179737)] [18]. Sorafenib is a multi-
kinase inhibitor targeting PDGF receptor (PDGFR), VEGF
receptor (VEGFR), c-kit, and Raf. In a mouse PH model, it has
been shown to prevent hemodynamic changes and attenuate
PH-associated vascular remodeling by abolishing the
upregulation of the mitogen-activated protein kinase (MAPK)
cascade [19]. In a clinical trial of 22 patients with PH, sorafenib
treatment generated a modest improvement in the exercise
capacity without any alteration in cardiac function [20]. It was
well tolerated at a 200-mg twice-daily dose, with the most
common adverse effects being moderate skin reaction and
alopecia.
However, there are reports showing that some other agents
in the family of TKIs induce PH. For example, treatment of
dasatinib in patients with leukemia induced PH [21–23].
Sugen5416, another protein kinase inhibitor, also induces PH
in rodents in combination with hypoxia exposure [24]. In
summary, although some TKIs offer promising new treat-
ments for PH, more studies are needed to understand how to
use them with minimal adverse effects and maximal efficacy.
2.2 Rho-Kinase Inhibitor
RhoA is a small monomeric G-protein that belongs to Ras
homologous (Rho) family. RhoA and its downstream
substrate Rho-kinase (ROCK) play significant roles in the
Developing Drugs for Pulmonary Hypertension
pathogenesis of PH, mediating vascular remodeling and
vasoconstriction [25–28]. Long-term inhibition of ROCK
with fasudil, a selective ROCK inhibitor, improved
pathological parameters of PH and pulmonary artery re-
modeling in monocrotaline- or hypoxia-induced rodent
models of PH [29–31]. Fasudil was the first ROCK in-
hibitor approved in 1995 for the treatment of subarachnoid
hemorrhage–induced brain vessel vasospasms [32, 33].
Clinical trials have shown that intravenous administration
of fasudil has acute beneficial vasodilatory effects on the
pulmonary circulation in PH patients [34, 35]. Inhalation of
fasudil was shown to be as effective as nitric oxide in-
halation in PH patients [36]. It was also reported that fa-
sudil reduced pulmonary artery pressure in patients with
high-altitude PH in a randomized, double-blind study [37].
AT-877ER (fasudil hydrochloride) is a specific ROCK
inhibitor with an extended-release formulation. It has been
used in a double-blind, placebo-controlled clinical trial to
treat PH in Japan. Although there was no significant dif-
ference observed in 6MWD between the AT-877ER group
and placebo group, the mid-term results showed improved
pulmonary hemodynamics and cardiac index in the AT-
877ER–treated group [38, 39].
2.3 Vasoactive Intestinal Peptide
Vasoactive intestinal peptide (VIP) is a neuropeptide hor-
mone that induces pulmonary vasodilation, inhibits vascular
SMC proliferation and platelet aggregation, and shows anti-
inflammatory properties [40–46]. Mediated by G-protein
coupled receptors (VPAC1, VPAC2, and PAC1), VIP can
stimulate the adenylate cyclase signaling pathway, activate
phospholipase-D, tyrosine kinases, and RhoA-GTPAses,
and increase intracellular calcium via calcium channel ac-
tivation. Downregulation of VIP has been proposed as one of
the defining features of PH on the basis of the observation of
pulmonary vascular remodeling and hypertension in VIP-
deficient mice and a reversal of the pathology with VIP re-
placement therapy [47]. Lungs from VIP knockout mice
showed increased expression of gene transcripts associated
with vasoconstriction/proliferation and inflammation, and
decreased expression of gene transcripts associated with
vasodilation/anti-proliferation. This gene expression profile,
however, was reversed to that seen in wild-type mice by VIP
treatment [48]. Interestingly, serum and pulmonary levels of
VIP are decreased in PH patients, but the expression levels of
VIP receptors are increased in PASMCs isolated from PH
patients [49]. A clinical trial of 20 PH patients receiving a
single inhalation dose of 100 lg aviptadil, an analog of VIP,
showed minimal side effects and yielded an acute and mild,
but statistically significant, decrease of pulmonary arterial
pressure with a significant increase in stroke volume and
mixed venous oxygen saturation [50]. A total of six patients
227
in this trial have been reported to have a reduction in PVR
of [20 %. Additionally, a combination of VIP and en-
dothelin receptor antagonist, bosentan, has been tested in
pre-clinical PH models. This combination therapy was more
effective than either drug alone, perhaps because of the
synergistic effects of both drugs on suppression of the en-
dothelin-endothelin (ET-ET) receptor pathway [51].
2.4 Selective Serotonin Reuptake Inhibitors
Upregulation of serotonin released from the pulmonary
endothelium is associated with the development of PH in
animal models, likely through its effects on pulmonary
vasoconstriction and SMC proliferation [52–61]. Selective
serotonin reuptake inhibitors (SSRIs) can attenuate and
even reverse the development of PH induced by chronic
hypoxia or monocrotaline in animal models [62–67].
Several clinical studies have suggested that SSRIs may be
associated with a decreased development of PH and mor-
tality in PH patients [68, 69]. However, one phase II
clinical trial failed to show the beneficial effects of SSRIs
(paroxetine, sertraline, or fluoxetine) in the treatment of
PH, while a separate trial showed that the use of SSRIs
correlated to even higher mortality and a greater risk of
clinical worsening [70, 71]. Because these trials may have
failed to appropriately match all clinical variables of the
treated and control patient populations, further studies are
necessary to conclusively determine whether SSRIs are an
appropriate therapeutic category for PH.
2.5 Endothelial Progenitor Cells
Since PH is associated with loss of or damage to the pul-
monary vascular endothelium, it has been theorized that the
delivery of additional endothelial progenitor cells (EPCs)
may provide a therapeutic benefit. The main sources of
EPCs are bone marrow and peripheral blood [72–78]. EPC
population is most commonly characterized through ex-
pression of CD34, CD133, and kinase domain receptor
(KDR) [79–81]. Some studies have suggested that patients
with PH had reduced peripheral EPCs [82–86]; however,
the relationship between the number of peripheral EPCs
and PH remains controversial [87–90]. EPCs derived from
hypoxia-derived PH mice were found to have altered
functions such as decreased migratory response to stromal
cell-derived factor-1a (SDF-1a), adhesion to fibronectin,
and incorporation into the vascular network [88]. It has
been demonstrated that treatment with autologous or um-
bilical cord blood-derived EPC can prevent and reverse PH
in small and large animal models, with improved hemo-
dynamics and amelioration in the medial thickness of the
small pulmonary arteries [78, 90, 91]. Studies in animal
models of PH have shown that EPCs transfected with genes
228 J. Hu et al.

of adrenomedullin [92] or endothelial nitric oxide synthase
(eNOS) [93] caused greater improvement in PH than EPCs
alone. The combination of EPCs and sildenafil therapy also
has synergistic effects when compared with a single
treatment with EPCs [94]. EPCs may benefit the prevention
of PH by vascular endothelial repair [95–97] and providing
protective paracrine effects [98–101]. Several clinical
studies have shown that EPC treatment is safe, feasible,
and can improve exercise capacity and hemodynamics [42,
44, 76, 77, 102]. There are two main types of EPCs; one is
colony-forming unit-Hill (CFU-Hill) cells, and the other
one is endothelial colony-forming cells (ECFCs). It has
been reported that ECFCs can form functional vessels
in vivo, while CFU-Hill cells cannot [103]. There is evi-
dence showing that CFU-Hill cells are hematopoietic cells
which may never become long-term intimal ECs in vivo
[103, 104]. Studies showed that the ECFCs could prevent
PH in rats treated with bleomycin [105], but no reports
have suggested CFU-Hill cells in preventing or improving
PH. While more clinical studies are needed to confirm the
safety, adverse effects, and efficacy of EPC treatment, it is
a novel approach for the future treatment of PH (Table 1).
2.6 Inflammation and Immunity
As perivascular inflammation is observed in patients and
animals with PH, several studies have assessed the role of
inflammation and immunity in the pathogenesis of PH.
Perivascular inflammatory infiltration is a complex inter-
play between T- and B-lymphocytes, macrophages, den-
dritic cells, and mast cells [106]. It was found that
inflammation precedes vascular remodeling in animal PH
models, which suggests that altered immunity is the cause
rather than a consequence of vascular disease [107]. In
addition, the circulating levels of cytokines and chemoki-
nes such as interleukin-1b (IL-1b), IL-6, IL-8, monocyte
chemoattractant protein 1 (MCP1), fractalkine, CCL5/
RANTES, and tumor necrosis factors-a (TNF-a) are in-
creased. These cytokines may lead to pulmonary vascular
remodeling by mediating or controlling proliferation, mi-
gration and differentiation of pulmonary vascular cells
[108]. In pre-clinical studies, targeting of several immune
mediators or processes, such as CD20, IL-1, transforming
growth factor-b (TGF-b), nuclear factor of activated T cells
(NFAT), tumor necrosis factor–related apoptosis-inducing
ligand (TRAIL), 5-lipoxygenase/5-lipoxygenase-activating
protein (5-LO/FLAP), Leukotriene B4 (LTB4), and purine
synthesis, has been shown to be effective in preventing or
even reversing PH [108]. Immunosuppressive agents such
as dexamethasone, mycophenolate mofetil, cyclosporine,
and etanercept have also been shown to improve PH in
animal models [109]. The highly selective elastase in-
hibitor elafin has been demonstrated to attenuate fully de-
veloped PAH in an animal model, with a significant

Table 1 Summary of the action of the drugs

Class Agent Mechanism of action

RTKI Imatinib Inhibition of PDGF, c-kit, and c-Abl receptors

Nilotinib Inhibition of BCR-ABL tyrosine kinase
Sorafenib Inhibition of PDGFR, VEGFR, c-kit, and Raf
Rho-kinase inhibitor AT-877ER (fasudil Inhibition of Rho-kinase
hydrochloride)
VIP Aviptadil Inducing pulmonary vasodilation, inhibiting vascular SMCs proliferation, platelet
aggregation
SSRI Paroxetine, sertraline, Inhibition of serotonin reuptake
fluoxetine
EPCs Repairing pulmonary vascular endothelium
Inflammation and Elafin Inhibition of elastase
immunity Bardoxolone methyl Inducing Nrf2 and suppressing NF-jB activation
Tacrolimus Inhibition of the NFAT family
Rituximab Antibody of CD20 on B cells
CCR5 Antagonist Maraviroc Inhibition of CCR5, protective effect on vascular lesions
Wnt Mesd (blocker of Wnt ligands) Competitively blocking the binding of Wnt ligands to LRP5/6
miRNAs MRX34 Mimic of miRNA tumor suppressor miR-34
Miravirsen Inhibitor of miRNA-122
CCR5 C-C motif chemokine receptor 5, EPC endothelial progenitor cell, LRP5/6 low-density lipoprotein receptor-related protein 5/6, miRNA
microRNA, NFAT nuclear factor of activated T cells, NF-kB nuclear factor kappa-light-chain-enhancer of activated B cells, Nrf2 nuclear factor
erythroid 2–related factor 2, PDGF platelet-derived growth factor, PDGFR PDGF receptor, RTKI receptor tyrosine kinase inhibitor, SMC smooth
muscle cell, SSRI selective serotonin reuptake inhibitor, VEGFR VEGF receptor, VIP vasoactive intestinal peptide
Developing Drugs for Pulmonary Hypertension
improvement of the vascular pathology, parameters of
pulmonary hemodynamics, and right ventricular function
[110]. In fact, elafin is an FDA-approved orphan drug for
the treatment of PH. Bardoxolone methyl (RTA402) is an
orally available semi-synthetic triterpenoid that induces
nuclear factor erythroid 2–related factor 2 (Nrf2) and
suppresses nuclear factor kappa-light-chain-enhancer of
activated B cells (NF-jB) activation. Bardoxolone methyl
can suppress activation of proinflammatory mediators,
enhance endothelial nitric oxide (NO) bioavailability, im-
prove metabolic dysfunction, inhibit vascular proliferation,
and prevent maladaptive remodeling. Bardoxolone methyl
also targets multiple cell types relevant to PH, including
ECs, SMCs, and macrophages. A phase II clinical trial is
currently underway to evaluate its efficacy as a therapeutic
for PH (NCT02036970) [111]. Recently, an inhibitor of the
NFAT family, FK506 (Tacrolimus), was reported to reverse
severe PH in the SUGEN/hypoxia model by restoring bone
morphogenetic protein type 2 receptor (BMPR2) signaling
[112], and its safety and efficacy are being evaluated in a
clinical trial (NCT01647945) [113]. Rituximab is a chimeric
monoclonal antibody recognizing CD20 on B cells and is
currently in use in a National Institute of Allergy and In-
fectious Diseases (NIAID)-sponsored trial (NCT01086540)
for the treatment of systemic sclerosis-associated PH [114].
However, no results have been reported yet for the clinical
trials utilizing bardoxolone methyl, FK506, or rituximab for
the treatment of PH. The effectiveness and safety of nu-
merous immune targets still need to be evaluated, and the
immunotherapies may have to be adjusted on a patient-by-
patient basis according to different subtypes of PH charac-
terized by distinct inflammatory profiles.
2.7 G-Protein-Coupled Receptor CCR5
CCR5 is strongly expressed in principal cell types impli-
cated in PH progression, including ECs, SMCs, T cells, and
macrophages [115–122]. It is considered a therapeutic
target in human immunodeficiency virus (HIV) infection
because it is a co-receptor for HIV cell entry [120, 122].
The CCR5 pathway also plays an important role in
atherogenesis, and studies have suggested that inhibition of
the CCR5 pathway has a protective effect on vascular le-
sions [117, 122]. Pulmonary expression of CCR5 is in-
creased in mice subjected to hypoxia-induced PH, as well
as in the explanted lungs from patients with idiopathic PH.
Notably, CCR5 expression is more marked in areas char-
acterized by greater severity of vascular medial hypertro-
phy. The activation of CCR5 leads to the proliferation of
cultured human PASMCs, while a human CCR5 antagonist
developed as an HIV therapeutic, maraviroc, inhibits this
proliferation [115]. It is reported that CCR5-deficient mice
developed less severe PH than wild-type mice after
229
hypoxia exposure, and maraviroc treatment markedly at-
tenuated hypoxia-induced PH development (distal pul-
monary artery muscularization) in CCR5 knock-in mice
[122]. In addition to the preventive effect, maraviroc can
also partially reverse PH in chronically hypoxic mice
[122]. Although no clinical trials evaluating the effects of
CCR5 inhibitors on PH have been reported, it may have
therapeutic potential for the treatment of PH.
2.8 Wnt Signaling
Wnt signaling has been linked to more than 20 clinical
diseases. Its effects in regulating angiogenesis and cell
growth have prompted researchers to hypothesize that it
can play a role in the treatment of PH in which none of the
current therapies can promote angiogenesis or reverse
medial thickening. Both the Wnt/b-catenin (Wnt/bC)
pathway and Wnt/planar cell polarity (Wnt/PCP) pathway
have been shown to be involved in the development of PH
[123–127]. Wnt7a and Wnt5 downregulate b-catenin and
have antiproliferative effects on PASMC cultured under
hypoxic conditions [127, 128]. In the lung tissue of PH
patients, it was found that the expression of PCP mediators
are upregulated, suggesting a pathophysiological role of the
Wnt/PCP pathway [129]. Low-density lipoprotein receptor-
related protein 5/6 (LRP5/6) are Wnt co-receptors that bind
to Wnt ligands and mediate canonical Wnt/bC signaling,
while Mesd is a cellular-encoded chaperone protein for
LRP5/6 that competitively blocks the binding of Wnt li-
gands to LRP5/6 [130]. Systemic delivery of Mesd protein
attenuated PH and pulmonary vascular remodeling in a
rodent model of hyperoxia-induced PH [131]. ICG001, a
novel b-catenin inhibitor, has been shown to increase
alveolarization and reduce pulmonary vascular remodeling
and PH in the rodent model of hyperoxia-induced PH.
ICG001 could also decrease PASMC proliferation and the
expression of extracellular matrix remodeling molecules
under hyperoxic conditions [132]. Gene expression array
analyses of different cell types from PH patients revealed
that molecular lesions associated with PH were present in
all cell types, and the Wnt signaling pathway was a com-
mon molecular defect in both heritable and idiopathic PH
[133]. However, due to a wide range of cellular functions
and molecular targets of Wnt signaling, extensive screen-
ing of Wnt modulators will be required to find therapeutic
candidates for PH that have minimal adverse effects and
toxicity with maximal efficacy.
2.9 MicroRNAs
MicroRNAs (miRNAs) are a category of small noncoding
RNAs, which regulate an array of proteins that affect many
biological processes including cell differentiation, survival,
230
Fig. 1 Drugs currently in discovery, development, and/or approved for the treatment of pulmonary hypertension. miRNA microRNA
and proliferation [134]. As many miRNAs are associated
with cancer development and have a potential as anti-cancer
agents, and because there are many overlapping pathways
(e.g., BMPR2, Src/STAT3/Pim1, and hypoxia) in both
cancer and PH [135, 136], the evaluation of miRNAs in PH
treatment remains an attractive idea. Some miRNAs are
thought to be modulators of signaling in pathogenic protein
expression, which leads to pulmonary vascular remodeling,
PH development, right ventricular (RV) hypertrophy, and
RV failure [137, 138]. There are two strategies for miRNA-
based therapies: miRNAs mimetics and miRNA antagonists.
Mimetics of miR-204, miR-424, miR-503, and let-7f are
reported to ameliorate or reverse PH in animal models [139–
141]. While miRNA antagonism may have more side effects
than miRNA mimetics, several studies have demonstrated
that specific miRNA antagonists, such as anti-miR-17, can
provide a beneficial therapy for PH [142]. Two drugs in this
category are being evaluated in clinical trials for other dis-
eases. MRX34, a mimic of miRNA tumor suppressor miR-
34, is being evaluated for treatment of liver cancer by in-
travenous (IV) delivery [143]. Miravirsen, an inhibitor of
miRNA-122, is in clinical trials for the treatment of hepatitis
C virus infection, via subcutaneous administration [144].
Currently, there are no clinical trials for miRNA-based
therapy for PH. However, further investigation may lead to
the development of novel and effective therapeutic
strategies.
J. Hu et al.
3 Summary
PH is a disease with complex and diverse underlying
mechanisms and a poor prognosis. In recent years, sig-
nificant progress has been made toward understanding the
pathophysiology and biochemistry of PH development,
which has led to considerable advances in the search for
new treatments. Alongside the refinement of existing
treatment strategies, many new molecular and cellular
pathways and targets involved in PH have been explored in
the development of new drugs and therapies (Fig. 1).
Although there are new therapies in pre-clinical or early-
stage clinical trials, most of the clinical trials conducted are
short term. More studies need to be conducted to assess the
safety and efficacy of such novel therapeutics before such
promising approaches can be added to our armamentarium
of treatments for PH.
Acknowledgments We thank Dr. Sergei Snovida for helpful com-
ments on the manuscript and Elfy Chiang for the graphic assistance.
Compliance with ethical standards There are no conflicts of in-
terests to declare for Jian Hu, Qinzi Xu, Charles McTiernan, Yen-
Chun Lai, and David Osei-Hwedieh. Mark Gladwin receives National
Institutes of Health (NIH) grant funding, and is a consultant for Bayer
for sickle cell disease. He is also the co-inventor of an NIH patent for
the use of nitrite for cardiovascular indications. He also receives
royalties as co-author of a textbook of medical students.
No financial assistance was received for preparing this manuscript.
Developing Drugs for Pulmonary Hypertension
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