US20170089924A1 - Method of testing for pulmonary hypertension - Google Patents

Method of testing for pulmonary hypertension Download PDF

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US20170089924A1
US20170089924A1 US15/305,879 US201515305879A US2017089924A1 US 20170089924 A1 US20170089924 A1 US 20170089924A1 US 201515305879 A US201515305879 A US 201515305879A US 2017089924 A1 US2017089924 A1 US 2017089924A1
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pulmonary hypertension
selenoprotein
protein
pulmonary
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Hiroaki Shimokawa
Kimio Satoh
Nobuhiro Kikuchi
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Tohoku University NUC
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Assigned to TOHOKU UNIVERSITY reassignment TOHOKU UNIVERSITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KIKUCHI, NOBUHIRO, SATOH, KIMIO, SHIMOKAWA, HIROAKI
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/12—Pulmonary diseases

Definitions

  • Pulmonary hypertension is a disease in which pulmonary artery blood pressure is increased due to a variety of causes. According to WHO classification or the like, pulmonary hypertension is classified into pulmonary arterial hypertension (PAH), pulmonary hypertension due to left heart disease, pulmonary hypertension due to lung disease and/or hypoxia, chronic thromboembolic pulmonary hypertension (CTEPH)), and pulmonary hypertension of unknown cause due to a combination of factors (Non-patent Literature (NPL) 1 to 5). In Japan, pulmonary hypertension includes many diseases designated as intractable diseases (specified diseases). In the case of patients at the terminal stage, lung transplantation may be necessary.
  • Pulmonary arterial hypertension is a lethal disease with a five-year survival rate of 20% in untreated patients. Early diagnosis is difficult, even for cardiologists. When diagnosed, patients are often already at the terminal stage. Although there are still no means other than lung transplantation for saving critically ill patients, the number of donors is limited, and there are many cases in which patients die while awaiting transplantation. The disease advances quickly in many younger-age cases, and death due to right heart failure frequently occurs, even when multidrug therapy is used. In recent years, there has been an increase in the number of pulmonary hypertension patients in Japan. However, the causes of this disease have yet to be fully clarified.
  • pulmonary hypertension can be accurately diagnosed, sufficient therapeutic effects can be expected.
  • therapeutic effects as well as prognostic improvement can be expected. For example, if pulmonary arterial hypertension is found at an early stage and an appropriate procedure is performed, the five-year survival rate is about 50%.
  • Selenoprotein P protein is one of the Se-containing proteins (a member of the selenoprotein family), and is a protein containing multiple selenocysteine residues. It has also been found that selenoprotein P protein is one of the causes of insulin resistance in type 2 diabetes, and that extracellular stimulation of selenoprotein P protein suppresses intracellular AMPK activity in hepatocytes (NPL 6). However, selenoprotein P protein, including its signaling pathway, remains largely unknown.
  • a main object of the present invention is to provide a method of testing for pulmonary hypertension, and, in particular, a method capable of easily and accurately testing for pulmonary hypertension.
  • the present invention further relates to a biomarker for detecting pulmonary hypertension, and a test kit for pulmonary hypertension.
  • the present inventors conducted extensive research to achieve the above. As a result, the inventor found that pulmonary hypertension can be tested by using as an indicator the concentration of selenoprotein P protein in a sample derived from a subject.
  • the present invention has been accomplished through further research based on this finding.
  • the present invention includes the following.
  • the present invention provides a method for easily and accurately testing for pulmonary hypertension. Because, for example, the testing method of the present invention can be performed by testing patients' blood, and can be performed on an outpatient basis, little burden is imposed on both patients and health care providers.
  • the testing method of the present invention is expected to allow pulmonary hypertension patients to be proactively tested, and thus receive effective therapy early.
  • the plasma concentration (ng/ml) of selenoprotein P protein in pulmonary hypertension patients increased. P ⁇ 0.001
  • FIG. 2 shows the results of detecting selenoprotein P protein in pulmonary blood vessel smooth muscle cells derived from idiopathic pulmonary arterial hypertension patients.
  • FIG. 2 shows the results of four independent trials under each of the following conditions: at normoxia; at hypoxia; and at hypoxia in the presence of fasudil (hypoxia+fasudil).
  • the upper column shows the detection of selenoprotein P protein in whole cell lysates by western blot analysis
  • the lower column shows the detection of selenoprotein P protein in conditioned medium by western blot analysis.
  • FIG. 4 shows the results of measuring the plasma concentration of selenoprotein P protein in patients with each type of pulmonary hypertension, which are shown in a box plot.
  • the asterisks and circles in FIG. 4 represent the outliers.
  • the testing method of the present invention is to test for pulmonary hypertension.
  • Pulmonary hypertension includes diseases in which increased pulmonary arterial pressure (mPAP, for example, 25 mmHg or more) is observed as a clinical observation.
  • Pulmonary hypertension include pulmonary arterial hypertension (PAH), pulmonary hypertension due to left heart disease, pulmonary hypertension due to lung disease and/or hypoxia, chronic thromboembolic pulmonary hypertension (CTEPH), other pulmonary hypertension of unknown cause due to a combination of factors, and the like.
  • PAH pulmonary arterial hypertension
  • CTEPH chronic thromboembolic pulmonary hypertension
  • pulmonary arterial hypertension An example of a pathological condition of pulmonary hypertension is pulmonary arterial hypertension.
  • pulmonary arterial hypertension examples include increased pulmonary artery pressure (mPAP, for example, 25 mmHg or more) and normal pulmonary wedge pressure (right atrial pressure) (PCWP, for example, 15 mmHg or less) (these can be measured, for example, by right heart catheterization); pulmonary blood flow distribution anomalies are not observed (these can be measured by, for example, lung ventilation-blood flow scintigraphy).
  • mPAP pulmonary artery pressure
  • PCWP right atrial pressure
  • pulmonary blood flow distribution anomalies are not observed (these can be measured by, for example, lung ventilation-blood flow scintigraphy).
  • Pulmonary arterial hypertension is a lethal disease in which blood vessel endothelial function deterioration, vascular smooth muscle cell growth, inflammatory cell infiltration, etc., have a complex interplay in the progression of wall-thickening or narrowing of pulmonary microvessels (pulmonary vascular remodeling). Its early diagnosis is difficult, even for cardiologists. When introduced to an institution for lung transplantation, patients are often already at the terminal stage. Although there are still no means other than lung transplantation for saving critically ill patients, the number of donors is limited, and there are many cases in which patients die while awaiting transplantation.
  • Idiopathic PAH idiopathic pulmonary arterial hypertension patients
  • IPAH idiopathic pulmonary arterial hypertension patients
  • advanced pulmonary artery remodeling characterized by abnormal growth of pulmonary artery vascular smooth muscle cells. Therefore, control of right heart failure is difficult, even with multidrug therapy, and there are still many cases in which patients die at a young age. Accordingly, early diagnosis and treatment are necessary before the clinical stage advances.
  • Pulmonary arterial hypertension includes pathological conditions such as idiopathic pulmonary arterial hypertension (IPAH)), heritable pulmonary arterial hypertension, drug/poison-induced pulmonary arterial hypertension, pulmonary arterial hypertension associated with other pathological conditions, persistent pulmonary hypertension of newborns, connective tissue disease, portopulmonary hypertension (portoPH), congenital heart diseases (shunt PAH), and the like.
  • IPH idiopathic pulmonary arterial hypertension
  • heritable pulmonary arterial hypertension pulmonary arterial hypertension
  • drug/poison-induced pulmonary arterial hypertension pulmonary arterial hypertension associated with other pathological conditions
  • persistent pulmonary hypertension of newborns connective tissue disease
  • portopulmonary hypertension portopulmonary hypertension
  • shunt PAH congenital heart diseases
  • NPL 1, NPL 7 The 2013 Nice Conference redefined pulmonary hypertension, and reclassified clinical classification (in this specification, this is referred to as “Nice Classification”) (NPL 1, NPL 7).
  • the testing method of the present invention uses as an indicator the concentration of selenoprotein P protein in a sample derived from a subject.
  • Testing includes testing for the presence or absence of pulmonary hypertension and testing for the risk of pulmonary hypertension.
  • testing refers to testing for the presence or absence of pulmonary hypertension.
  • Trusting for the risk includes testing and determination of the presence or absence of a probability of developing pulmonary hypertension in the future. “Testing” can be paraphrased as “determination” or “diagnosis.”
  • the sample is obtained from a subject.
  • the sample is derived from a subject to be tested by the testing method.
  • the subject is not particularly limited, and examples thereof include mammals including humans. Examples of non-human mammals include mice, rats, dogs, cats, cattle, sheep, horses, and the like.
  • the subject of the testing method of the present invention is preferably a human.
  • examples of subjects include patients having any subjective symptom that is characteristic of pulmonary hypertension, such as shortness of breath during exertion, or chest discomfort, and preferably patients suspected to have pulmonary hypertension.
  • the subject When the subject is a human, the sex, age, and race of the subject are not particularly limited.
  • the subject is an Asian person (e.g., Japanese, Chinese, or South Korean) and is particularly preferably Japanese.
  • the subject is female in view of a statistically larger number of patients.
  • the sample is preferably a blood sample derived from the subject.
  • the blood sample include blood (whole blood), blood-derived serum and plasma, and the like.
  • the blood sample is preferably plasma.
  • Plasma is a part of blood obtained by removing corpuscular components from blood. For example, it can be obtained as a supernatant when subjected to centrifugal separation under conditions in which blood is not solidified (for example, in the presence of sodium citrate).
  • the blood vessel from which the blood sample is derived is not limited.
  • the blood can be collected from a systemic circulation blood vessel (arteries (peripheral arteries), veins (peripheral veins), and capillaries) or a pulmonary circulation blood vessel (pulmonary arteries, pulmonary veins, and pulmonary capillaries). From the viewpoint of collecting blood easily, it is preferable that the blood is collected from a systemic circulation blood vessel, in particular, from a vein (peripheral vein). Blood can be collected from a pulmonary circulation blood vessel upon right heart catheterization.
  • the testing method of the present invention preferably comprises the steps of:
  • the concentration of selenoprotein P (SeP) protein in a sample is used as an indicator.
  • Selenoprotein P protein is a known protein.
  • Human selenoprotein P protein is one of the Se-containing proteins (a member of selenoprotein family) encoded on the selenoprotein P, plasma, 1 (SEPP1) gene locus, and is a protein containing multiple selenocysteine residues.
  • Selenoprotein P protein is known to mainly secrete from the liver extracellularly.
  • the “P” in the term refers to “plasma.”
  • Selenoprotein P protein is known to be a cause of insulin resistance in type 2 diabetes mellitus. It has also been found that extracellular stimulation of selenoprotein P protein suppresses intracellular AMPK activity in hepatocytes (NPL 6). However, selenoprotein P protein, including its signaling pathway, remains largely unknown. In particular, selenoprotein P protein's involvement in pulmonary hypertension is unknown.
  • amino acid sequences of human ( Homo sapiens ) selenoprotein P protein and mouse ( Mus musculus ) selenoprotein P protein have been registered at GenBank provided by the National Center for Biotechnology Information (NCBI), under the following accession numbers (it should be understood that when multiple revisions have been registered, each number refers to the latest revision):
  • the means for measuring the blood concentration of selenoprotein P protein can be suitably selected by persons skilled in the art.
  • preferable means include immunoassay using an antibody specifically detecting selenoprotein P protein (i.e., an antibody specifically binding to selenoprotein P protein) (including full length of antibody (immunoglobulin protein) molecules and fragments such as F(ab) and F(ab′) 2 ).
  • immunoassay include ELISA, EIA, western blot, and the like. Among these, techniques that can perform a quantitative test, such as ELISA, are preferable.
  • the antibody that can be used in immunoassay is not particularly limited as long as it can specifically detect selenoprotein P protein in a sample.
  • the concentration of selenoprotein P protein in a sample can also be measured by using a commercially available reagent.
  • a commercially available product can be used as a reagent for determining the concentration of selenoprotein P protein in a sample.
  • commercially available products include, but are not limited to, a Human Selenoprotein P, SEPP1 ELISA Kit (produced by Cusabio, Model No.: CSB-EL021018HU).
  • antibodies for detecting selenoprotein P protein commercially available antibodies specifically binding to anti-selenoprotein P, such as an anti-selenoprotein P antibody (produced by Santa Cruz Biotechnology, Model No.: sc-30162), can also be used.
  • the determined concentration of selenoprotein P protein in a sample may be an absolute value and a relative value.
  • an absolute value of the selenoprotein P protein concentration in a sample is determined.
  • the presence or absence of and/or the risk of pulmonary hypertension can be assessed, based on the measured concentration of selenoprotein P protein in samples.
  • the assessment criteria for the testing method can be suitably selected by persons skilled in the art.
  • a predetermined cutoff value can be used as assessment criteria. For example, when the concentration of selenoprotein P protein is used as an indicator, if the concentration of selenoprotein P protein in a sample is higher than a predetermined cutoff value, the patient can be determined to have pulmonary hypertension, or have a probability of developing pulmonary hypertension.
  • the cutoff value can be determined by various statistical analysis techniques. Examples of the cutoff value include a median or mean value in pulmonary hypertension, a value determined based on ROC curve analysis (e.g., Youden's index), and the like. Multiple cutoff values can also be set.
  • the cutoff value can be set to, for example, about 10 ⁇ g/ml.
  • concentration of selenoprotein P protein in healthy subjects is usually in the range of about 3 to 8 ⁇ g/ml.
  • the testing method of the present invention may be combined with another known or future testing method for pulmonary hypertension.
  • the testing method may comprise a step of measuring a tricuspid regurgitation pressure gradient (TRPG) in a subject.
  • TRPG can be measured by cardiac ultrasonography.
  • the TRPG refers to a difference between a pressure of blood squeezed out of the heart and a pressure of blood having passed through the valve, which can be calculated by echocardiography.
  • the TRPG is about 50 mmHg or more, the subject can be determined to have a high probability of having pulmonary hypertension.
  • the subject can be determined to have a high probability of having pulmonary hypertension not only when the TRPG is about 50 mmHg or more, but also when the TRPG is about 50 mmHg or less and the measured concentration of selenoprotein P protein in a sample is equal to or higher than a predetermined cutoff value.
  • Pulmonary hypertension in a subject is thus tested.
  • the subject determined to have pulmonary hypertension or have a risk of developing pulmonary hypertension by the testing method of the present invention is preferably subjected to a thorough examination of the presence or absence of pulmonary hypertension and/or identification of a lesion by right cardiac catheterization, lung ventilation-blood flow scintigraphy, chest computed tomography (CT), lung arteriography, optical coherence tomography (OCT), or the like.
  • CT chest computed tomography
  • OCT optical coherence tomography
  • the patient determined to have a high probability of having pulmonary hypertension by a thorough examination is preferably subjected to an appropriate procedure for treating and/or preventing progression of pulmonary hypertension.
  • appropriate procedures include administration of endothelin receptor antagonists (e.g., bosentan, ambrisentan), administration of prostaglandin I 2 (prostacyclin) preparations, administration of phosphodiesterase-5 (PDE-5) inhibitors (e.g., sildenafil and tadalafil), and the like.
  • PDE-5 phosphodiesterase-5
  • combination therapy in particular, triple-combination therapy, is preferable.
  • the present invention further provides a kit for testing for pulmonary hypertension.
  • the kit of the present invention includes a means for measuring the concentration of selenoprotein P protein in a sample derived from a subject.
  • Examples of means for measuring the concentration of selenoprotein P protein include the above-mentioned means for performing immunoassay etc. using an antibody that specifically detects selenoprotein P protein.
  • Specific examples include antibodies that specifically detect selenoprotein P protein and/or other reagents for performing immunoassay, such as ELISA, EIA, or western blot.
  • the kit of the present invention may further include other components, if necessary.
  • other components include, but are not limited to, instruments for collecting a sample (e.g., syringes), positive control samples (e.g., samples derived from patients confirmed to have pulmonary hypertension), negative control samples (e.g., samples derived from patients confirmed not to have pulmonary hypertension (healthy subjects)), and the like.
  • the kit may also include a procedure manual for performing the test method.
  • the kit of the present invention can be produced by appropriately preparing the above-mentioned components according to a usual method.
  • the kit is preferably used in the testing method described above.
  • the testing for pulmonary hypertension can easily be conducted.
  • the present invention further provides a method for treating pulmonary hypertension.
  • the “treatment” or “treating” as used herein includes treatments for pulmonary hypertension and maintenance therapies for symptomatic relief and recurrence prevention.
  • the method for treatment of the present invention comprises the steps of:
  • step (i) the testing method described in the above-mentioned section “1. Method of Testing for Pulmonary Hypertension” is performed.
  • step (ii) the subject in whom pulmonary hypertension was detected is subjected to a treatment for treating pulmonary hypertension and/or preventing progression of pulmonary hypertension.
  • steps (i) and (ii) there may be conducted a thorough examination of the presence or absence of a cardiovascular disease and/or identification of a lesion by a thorough examination, such as cardiac catheterization or angiography (including X-ray angiography, computed tomographic (CT) angiography, and nuclear magnetic resonance (MR) angiography).
  • cardiac catheterization or angiography including X-ray angiography, computed tomographic (CT) angiography, and nuclear magnetic resonance (MR) angiography.
  • a procedure for treating pulmonary hypertension and/or preventing progression of a cardiovascular disease a known appropriate procedure is performed.
  • procedures include, for example, administration of endothelin receptor antagonists (e.g., bosentan, ambrisentan); administration of prostaglandin I 2 (prostacyclin) preparations; administration of phosphodiesterase-5 (PDE-5) inhibitors (e.g., sildenafil and tadalafil); and the like.
  • PDE-5 phosphodiesterase-5
  • the plasma concentration of selenoprotein P protein in pulmonary hypertension patients and non-pulmonary hypertension patients was measured.
  • the pulmonary hypertension patients as subjects were patients diagnosed as having pulmonary arterial hypertension.
  • the blood sampled from the following patient groups was subjected to testing.
  • Plasma was separated from peripheral vein-derived blood samples and pulmonary artery-derived blood samples obtained from the above-mentioned patient groups at right heart catheterization.
  • the plasma concentration of selenoprotein P protein was measured by ELISA using a Human Selenoprotein P, SEPP1 ELISA kit (produced by Cusabio Inc.; Model No. CSB-EL021018HU).
  • FIG. 1 shows the results. As shown in FIG. 1 , it became clear that pulmonary hypertension patients have a plasma concentration of selenoprotein P protein significantly higher than that of non-pulmonary hypertension patients.
  • the plasma concentration of selenoprotein P protein was measured in pulmonary hypertension patients and in non-pulmonary hypertension patients in the same manner as in Example 1.
  • Plasma was separated from the blood samples obtained from the above patient groups in the same manner as in Example 1. The selenoprotein P protein concentration in plasma was measured.
  • FIGS. 3 and 4 show the results.
  • FIG. 3 shows the measurement results of all of the pulmonary hypertension patients.
  • FIG. 4 shows the results of each type of pulmonary hypertension. The results revealed that irrespective of the type of pulmonary hypertension, all types of pulmonary hypertension patients had a significantly higher plasma concentration of selenoprotein P protein than non-pulmonary hypertension patients.
  • IPAH-PASMC pulmonary artery smooth muscle cells
  • IPAH-PASMC was cultured in D-MEM medium supplemented by 10% FBS (fetal bovine serum) at 37° C. under constant temperature and constant humidity conditions at 95% air and 5% CO 2 in accordance with a usual method. In this test, passage 4 to 7 cells at a confluence of 70 to 80% were used.
  • FBS fetal bovine serum
  • the cells to be used for the test were cultured for 24 hours under one of the following conditions: at normoxia (oxygen concentration: 21%); at hypoxia (oxygen concentration: 2%); and at hypoxia in the presence of fasudil (hydroxyfasudil concentration: 10 ⁇ M).
  • FIG. 2 shows the results. It became clear that the pulmonary blood vessel smooth muscle cells derived from idiopathic pulmonary arterial hypertension patients promote extracellular secretion of selenoprotein P protein (into the medium) at hypoxia than at normoxia. In the presence of fasudil, which is an inhibitor of Rho kinase (ROCK), enhanced secretion of selenoprotein P protein was not observed, even at hypoxia.
  • fasudil which is an inhibitor of Rho kinase (ROCK)

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