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Aging and disease
Orginal Article |
Pathological Mechanisms and Potential Therapeutic Targets of Pulmonary Arterial Hypertension: A Review
Ying Xiao1, Pei-Pei Chen1, Rui-Lin Zhou2, Yang Zhang1, Zhuang Tian1,*, Shu-Yang Zhang1,*
1Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
2School of Medicine, Tsinghua University, Beijing 100084, China
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Abstract  

Pulmonary arterial hypertension (PAH) is a progressive cardiovascular disease characterized by pulmonary vasculature reconstruction and right ventricular dysfunction. The mortality rate of PAH remains high, although multiple therapeutic strategies have been implemented in clinical practice. These drugs mainly target the endothelin-1, prostacyclin and nitric oxide pathways. Management for PAH treatment includes improving symptoms, enhancing quality of life, and extending survival rate. Existing drugs developed to treat the disease have resulted in enormous economic and healthcare liabilities. The estimated cost for advanced PAH has exceeded $200,000 per year. The pathogenesis of PAH is associated with numerous molecular processes. It mainly includes germline mutation, inflammation, dysfunction of pulmonary arterial endothelial cells, epigenetic modifications, DNA damage, metabolic dysfunction, sex hormone imbalance, and oxidative stress, among others. Findings based on the pathobiology of PAH may have promising therapeutic outcomes. Hence, faced with the challenges of increasing healthcare demands, in this review, we attempted to explore the pathological mechanisms and alternative therapeutic targets, including other auxiliary devices or interventional therapies, in PAH. The article will discuss the potential therapies of PAH in detail, which may require further investigation before implementation.

Keywords pulmonary arterial hypertension      right ventricular dysfunction      hemodynamics      therapy advances     
Corresponding Authors: Zhuang Tian,Shu-Yang Zhang   
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These authors contributed equally to this work.

Just Accepted Date: 16 January 2020  
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Ying Xiao
Pei-Pei Chen
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Shu-Yang Zhang
Cite this article:   
Ying Xiao,Pei-Pei Chen,Rui-Lin Zhou, et al. Pathological Mechanisms and Potential Therapeutic Targets of Pulmonary Arterial Hypertension: A Review[J]. Aging and disease, 10.14336/AD.2020.0111
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http://www.aginganddisease.org/EN/10.14336/AD.2020.0111     OR     http://www.aginganddisease.org/EN/Y/V/I/0
GeneGene IDChromosomeDiseaseFunctionNameRefs
BMPR26592q33.1-q33.2IPAH
HPAH
Member of the TGF-β receptor familyBone morphogenetic protein receptor type 2[29]
[19]
ACVRL19412q13.13HHT/PAH
HPAH
Receptor for the TGF-β superfamilyActivin A receptor-like type 1 (ALK1)[116]
[117]
ENG20229q34.11HHT/PAHCoreceptor of the TGF-β familyEndoglin[118]
SMAD9409313q13.3HPAHTransduces signals from the TGF-β familySMAD family member 9[119]
KCNK337772p23.3HPAH
IPAH
Encodes the TASK-1 channel, contributes to the membrane potentialPotassium two-pore domain channel subfamily K member 3[120]
EIF2AK444027515q15.1PVOD/PCHPhosphorylates eukaryotic translation initiation factor-2 (EIF2)Eukaryotic translation initiation factor 2 alpha kinase 4[121]
TBX4949617q23.2Small patella syndrome,
PAH in children
Involved in the development of lung diseaseT-box 4[14]
[122]
BMP9265810q11.22HPAH
IPAH
Binds the TGF-β receptorBone morphogenetic protein 9 or growth differentiation factor 2
[15]
Table 1  Gene variants associated with pulmonary arterial hypertension.
Figure 1.  Activation of BMP signaling with or without mutated BMPR2 and the pharmacological mechanism of FK506. BMP signaling in the presence of normal or mutated dysfunctional BMPR2. Mutated BMPR2 protein disturbs the dissociation of FKBP12-calcineurin from BMPR1 when stimulated by activating doses of BMPs. FK506 binds to FKBP12 and promotes the dissociation of FKBP12-calcineurin from BMPR type 1 receptors and then activates the downstream signaling pathway. BMP: bone morphogenetic protein; FKBP12: FK506-binding protein 12.
Drug/agentMechanismClinicalTrials.gov
identifier
ParticipantsStudy designStudy durationPrimary outcome measureOutcome
Tacrolimus (FK506)Activator of BMP signalingNCT0164794523 patients with PAHSingle center, phase Ⅱ randomized, placebo-controlled study16 weeksSafety of low-dose FK-506 in PAHCompleted
TocilizumabHumanized anti-IL6R antibodyNCT0267694729 patients with group 1 PAHOpen-label phase II trial6 monthsSafety in terms of the incidence and severity of adverse eventsCompleted
AnakinraRecombinant IL-1 receptor antagonistNCT030570286 patients with stable PAH and RV failureSingle-arm, open-label, phase IB/II pilot study14 daysChange in exercise capacity as determined by peak oxygen consumption and ventilatory efficiencyCompleted
RituximabAnti-CD20 antibodyNCT01086540SSc-PAHDouble-blind, placebo-controlled, phase Ⅱ, multicenter, randomized trial48 weeksChange from baseline in 6MWDActive, not recruiting
Dichloroacetic acid
(DCA)
Inhibition of pyruvate dehydrogenase kinaseNCT0108352420 adult patients with IPAHPhase I, open-label, two-center study28 weeksSafety and tolerability of DCACompleted
Apabetalone (RVX-208)BET inhibitorNCT03655704Estimated 10 participantsEarly phase Ⅰ, two-center, open-label trial16 weeksChange in PVRRecruiting
OlaparibPARP1 inhibitorNCT03251872Estimated 6 participantsOpen-label, early phase I trial16 weeksChange in PVRRecruiting
AnastrozoleEstrogen inhibitorNCT0154533618 participantsDouble-blind, placebo-controlled, phase II study3 monthsPlasma estradiol (E2) level, tricuspid annular plane systolic excursion (TAPSE)Completed
MetforminMultifunctional aromatase inhibitor and AMPK activatorNCT03617458160 participantsPhase II, 2x2 factorial, randomized, blinded trial12 weeksChange from baseline in 6MWDRecruiting
ImatinibSelective tyrosine kinase inhibitorNCT0139249517 participantsOpen-label, phase III, nonrandomized trial144 weeksNumber of patients with adverse event and deathsTerminated for severe adverse effects
Dimethyl fumarateNuclear factor erythroid 2-related factor 2 (Nrf2) activatorNCT0298108234 participants with SSc-PAHDouble-blinded, phase I, placebo-controlled pilot study24 weeksImprovement in 6MWDRecruiting
Bardoxolone methylNrf2 pathway-activating agentNCT02657356202 participants with CTD-PAHPhase III, double-blind, randomized, placebo-controlled trial24 weeksChange from baseline in 6MWDNot recruiting
Gene-enhanced EPCs (PHACeT trial)Cell therapyNCT004690277 participants with PAHPhase I, open-label, dose-escalation study5 yearsTolerability and safety of the injection of genetically engineered progenitor cellsCompleted
Pulmonary artery denervation (PADN)Inhibitor of sympathetic stimulationNCT02284737Estimated 270 participantsPhase IV, prospective, multicenter, randomized control trial6 monthsPAH-related events, death including lung transplantation, atrial septostomy, worsening of PAHRecruiting
Table 2  Clinical trials and potential therapeutic targets in pulmonary arterial hypertension.
Figure 2.  Pathobiology of PAH and potential therapeutic targets. Pathological mechanisms and potential therapeutic targets of PAH. The pulmonary artery wall consists of three structural layers, including the adventitia, media, and intima. Various pathogenic factors, such as gene mutations, drugs/poisons, and hypoxia, can induce pulmonary arteriole vascular vasoconstriction, characterized by luminal stenosis, endothelial dysfunction, inflammation, infiltration, etc., ultimately causing RHF. The endothelin-1, prostacyclin, and nitric oxide pathways have been targeted in clinical practice and are three pivotal pathways approved in PAH management. Potential therapeutic targets are emerging as the pathobiology of PAH is revealed. AS: atrial septostomy; BAS: balloon atrial septostomy; PADN: pulmonary artery denervation; ECMO: extracorporeal membrane oxygenation.
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