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      Effect of Small Hairpin RNA Targeting Endothelin-Converting Enzyme-1 in Monocrotaline-Induced Pulmonary Hypertensive Rats

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          Abstract

          The purpose of this study was to investigate the therapeutic effects of small hairpin RNA (shRNA) targeting endothelin-converting enzyme (ECE)-1 in monocrotaline (MCT)-induced pulmonary hypertensive rats. Ninty-four Sprague-Dawley rats were divided into three groups: control (n = 24), MCT (n = 35) and shRNA (n = 35). Four-week survival rate in the shRNA group was significantly increased compared to that in the MCT group. The shRNA group showed a significant improvement of right ventricular (RV) pressure compared with the MCT group. The MCT and shRNA groups also showed an increase in RV/(left ventricle + septum) ratio and lung/body weight. Plasma endothelin (ET)-1 concentrations in the shRNA group were lower than those in the MCT group. Medial wall thickness of pulmonary arterioles were increased after MCT injection and was significantly decreased in the shRNA group. The number of intra-acinar muscular pulmonary arteries was decreased in the shRNA group. The mRNA expressions of ET-1 and ET receptor A (ET A) were significantly decreased in the shRNA group in week 4. The protein levels of ET A were decreased in the shRNA group in week 2. The protein levels of tumor necrosis factor-α and vascular endothelial growth factor were decreased in the shRNA group in week 4. In conclusion, the gene silencing with lentiviral vector targeting ECE-1 could be effective against hemodynamic, histopathological and gene expression changes in pulmonary hypertension.

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          Most cited references29

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          Survival in patients with primary pulmonary hypertension. Results from a national prospective registry.

          G D'Alonzo, R Barst, S. Ayres … (1991)
          To characterize mortality in persons diagnosed with primary pulmonary hypertension and to investigate factors associated with survival. Registry with prospective follow-up. Thirty-two clinical centers in the United States participating in the Patient Registry for the Characterization of Primary Pulmonary Hypertension supported by the National Heart, Lung, and Blood Institute. Patients (194) diagnosed at clinical centers between 1 July 1981 and 31 December 1985 and followed through 8 August 1988. At diagnosis, measurements of hemodynamic variables, pulmonary function, and gas exchange variables were taken in addition to information on demographic variables, medical history, and life-style. Patients were followed for survival at 6-month intervals. The estimated median survival of these patients was 2.8 years (95% Cl, 1.9 to 3.7 years). Estimated single-year survival rates were as follows: at 1 year, 68% (Cl, 61% to 75%); at 3 years, 48% (Cl, 41% to 55%); and at 5 years, 34% (Cl, 24% to 44%). Variables associated with poor survival included a New York Heart Association (NYHA) functional class of III or IV, presence of Raynaud phenomenon, elevated mean right atrial pressure, elevated mean pulmonary artery pressure, decreased cardiac index, and decreased diffusing capacity for carbon monoxide (DLCO). Drug therapy at entry or discharge was not associated with survival duration. Mortality was most closely associated with right ventricular hemodynamic function and can be characterized by means of an equation using three variables: mean pulmonary artery pressure, mean right atrial pressure, and cardiac index. Such an equation, once validated prospectively, could be used as an adjunct in planning treatment strategies and allocating medical resources.
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            Expression of endothelin-1 in the lungs of patients with pulmonary hypertension.

            A Giaid, M Yanagisawa, D. Langleben … (1993)
            Pulmonary hypertension is characterized by an increase in vascular tone or an abnormal proliferation of muscle cells in the walls of small pulmonary arteries. Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide with important mitogenic properties. It has therefore been suggested that endothelin-1 may contribute to increases in pulmonary arterial tone or smooth-muscle proliferation in patients with pulmonary hypertension. We studied the sites and magnitude of endothelin-1 production in the lungs of patients with various causes of pulmonary hypertension. We studied the distribution of endothelin-1-like immunoreactivity (by immunocytochemical analysis) and endothelin-1 messenger RNA (by in situ hybridization) in lung specimens from 15 control subjects, 11 patients with plexogenic pulmonary arteriopathy (grades 4 through 6), and 17 patients with secondary pulmonary hypertension and pulmonary arteriopathy of grades 1 through 3. In the controls, endothelin-1-like immunoreactivity was rarely seen in vascular endothelial cells. In the patients with pulmonary hypertension, endothelin-1-like immunoreactivity was abundant, predominantly in endothelial cells of pulmonary arteries with medial thickening and intimal fibrosis. Likewise, endothelin-1 messenger RNA was increased in the patients with pulmonary hypertension and was expressed primarily at sites of endothelin-1-like immunoreactivity. There was a strong correlation between the intensity of endothelin-1-like immunoreactivity and pulmonary vascular resistance in the patients with plexogenic pulmonary arteriopathy, but not in those with secondary pulmonary hypertension. Pulmonary hypertension is associated with the increased expression of endothelin-1 in vascular endothelial cells, suggesting that the local production of endothelin-1 may contribute to the vascular abnormalities associated with this disorder.
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              Primary pulmonary hypertension.

              Daniel L Rubin (1997)
              Article 0 comments Cited 169 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Korean Med Sci
                Journal ID (iso-abbrev): J. Korean Med. Sci
                Journal ID (publisher-id): JKMS
                Title: Journal of Korean Medical Science
                Publisher: The Korean Academy of Medical Sciences
                ISSN (Print): 1011-8934
                ISSN (Electronic): 1598-6357
                Publication date (Print): December 2012
                Publication date (Electronic): 07 December 2012
                Volume: 27
                Issue: 12
                Pages: 1507-1516
                Affiliations
                [1 ]Department of Pediatrics, Konkuk University School of Medicine, Seoul, Korea.
                [2 ]Department of Thoracic and Cardiovascular Surgery, Ewha Womans University School of Medicine, Seoul, Korea.
                [3 ]Department of Physiology, Konkuk University School of Medicine, Chungju, Korea.
                [4 ]Department of Pathology, Ewha Womans University School of Medicine, Seoul, Korea.
                [5 ]Department of Pediatrics, Ewha Womans University School of Medicine, Seoul, Korea.
                Author notes
                Address for Correspondence: Young Mi Hong, MD. Department of Pediatrics, Ewha Womans University School of Medicine, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul 158-710, Korea. Tel: +82.2-2650-2841, Fax: +82.2-2653-3718, hongym@ 123456chollian.net

                *Jae Sung Son and Kwan Chang Kim contributed equally to this work.

                Article
                DOI: 10.3346/jkms.2012.27.12.1507
                PMC ID: 3524430
                PubMed ID: 23255850
                SO-VID: 9771748b-891a-4307-aaa7-7fd0ca1b3969
                Copyright © © 2012 The Korean Academy of Medical Sciences.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 29 May 2012
                Date accepted : 31 October 2012
                Categories
                Subject: Original Article
                Subject: Cardiovascular Disorders

                ScienceOpen disciplines: Medicine
                Keywords: hypertension, pulmonary,monocrotaline,small hairpin rna,lentivirus,endothelin-converting enzyme,rna, small interfering
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: hypertension, pulmonary, monocrotaline, small hairpin rna, lentivirus, endothelin-converting enzyme, rna, small interfering

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