Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Molecular Medicine Reports
Join Editorial Board Propose a Special Issue
Print ISSN: 1791-2997 Online ISSN: 1791-3004
Journal Cover
October 2014 Volume 10 Issue 4

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
October 2014 Volume 10 Issue 4

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Dichloroacetate prevents but not reverses the formation of neointimal lesions in a rat model of severe pulmonary arterial hypertension

  • Authors:
    • Bingbing Li
    • Jie Yan
    • Yan Shen
    • Yong Liu
    • Zhengliang Ma
  • View Affiliations / Copyright

    Affiliations: Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China, The State Key Laboratory of Reproductive Medicine, Department of Anesthesiology, The Nanjing Maternity and Child Health Care Hospital Affiliated with Nanjing Medical University, Nanjing, Jiangsu 210004, P.R. China, Jiangsu Key Laboratory for Molecular Medicine, Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China
  • Pages: 2144-2152
    |
    Published online on: July 30, 2014
       https://doi.org/10.3892/mmr.2014.2432
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

The formation of neointimal lesions is one of the characteristic pathological alterations of the pulmonary vasculature in response to sustained pulmonary arterial hypertension (PAH). To date, the effect of dichloroacetate (DCA) on these intimal lesions had remained to be investigated. In the present study, the beneficial impact of DCA on the formation of neointimal lesions was examined in rats treated with monocrotaline following pneumonectomy. The rats were subjected to monocrotaline subcutaneous injection seven days following left pneumonectomy and received DCA by gastric gavage (80 mg/kg/day) for 20 days. At the end of the experiments, hemodynamic measurement was performed prior to the excision of the rats' right lungs for further morphometric and immunoblot analysis. Furthermore, the activity of reactive oxygen species (ROS), superoxide dismutase (SOD) in the lungs was examined by a colorimetric assay. The results revealed that DCA treatment from day 8-28 following pneumonectomy caused a marked reduction in pulmonary arterial pressure and amelioration in right ventricle hypertrophy (mean pulmonary arterial pressure, 24±2.8 vs. 33±5.5 mmHg; right ventricle-to-left ventricle + intra-ventricle septum ratio, 29±2.8 vs. 43±3.3%; P<0.05) and pulmonary arterioles intimal proliferation (grade 1 and 2 occlusion, 24 and 20% vs. 44 and 40%; P<0.05) in pulmonary hypertensive rats. By contrast, DCA treatment initiated 29 days following pneumonectomy did not result in any improvement in pulmonary circulatory parameters or regression of occlusive neointimal lesions. Immunohistochemical and immunoblot assays demonstrated markedly reduced hypoxia inducible factor (HIF-1α) levels, and increased voltage-dependent potassium channel subtype 1.5 (Kv1.5) expression levels were observed in those neointimal regions in rats receiving DCA preventive therapy. Furthermore, preventive treatment with DCA significantly increased the activity of copper/zinc superoxide dismutase (Cu/Zn SOD activity, 88±4.2 vs. 53±2.7 U/mgprot; P<0.05) and promoted the degradation of ROS (106±4.7 vs. 79±13.3 U/mgprot; P<0.05), which was compromised in the delayed intervention group. Therefore, DCA is effective to prevent the formation of intimal lesions, which may be attributed to the induction of the upregulation of Cu/Zn SOD activity and the suppression of HIF-1α activation.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

View References

1 

McLaughlin VV, Davis M and Cornwell W: Pulmonary arterial hypertension. Curr Probl Cardiol. 36:461–517. 2011. View Article : Google Scholar : PubMed/NCBI

2 

Tuder RM: Pathology of pulmonary arterial hypertension. Semin Respir Crit Care Med. 30:376–385. 2009. View Article : Google Scholar

3 

Stamm JA, Risbano MG and Mathier MA: Overview of current therapeutic approaches for pulmonary hypertension. Pulm Circ. 1:138–159. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Stacpoole PW, Nagaraja NV and Hutson AD: Efficacy of dichloroacetate as a lactate-lowering drug. J Clin Pharmacol. 43:683–691. 2003. View Article : Google Scholar : PubMed/NCBI

5 

McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, et al: Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res. 95:830–840. 2004. View Article : Google Scholar : PubMed/NCBI

6 

Michelakis ED, McMurtry MS, Wu XC, Dyck JR, Moudgil R, Hopkins TA, et al: Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation. 105:244–250. 2002. View Article : Google Scholar

7 

Guignabert C, Tu L, Izikki M, Dewachter L, Zadigue P, Humbert M, et al: Dichloroacetate treatment partially regresses established pulmonary hypertension in mice with SM22alpha-targeted overexpression of the serotonin transporter. FASEB J. 23:4135–4147. 2009. View Article : Google Scholar

8 

Michelakis ED, Webster L and Mackey JR: Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer. 99:989–994. 2008. View Article : Google Scholar : PubMed/NCBI

9 

Wong JY, Huggins GS, Debidda M, Munshi NC and De Vivo I: Dichloroacetate induces apoptosis in endometrial cancer cells. Gynecol Oncol. 109:394–402. 2008. View Article : Google Scholar : PubMed/NCBI

10 

Washington JT and Quintyne NJ: Dichloroacetate induces different rates of cell death in cancer and noncancer cell lines in vitro. Tumori. 98:142–151. 2012.PubMed/NCBI

11 

Saed GM, Fletcher NM, Jiang ZL, Abu-Soud HM and Diamond MP: Dichloroacetate induces apoptosis of epithelial ovarian cancer cells through a mechanism involving modulation of oxidative stress. Reprod Sci. 18:1253–1261. 2011. View Article : Google Scholar : PubMed/NCBI

12 

Semenza GL: Involvement of hypoxia-inducible factor 1 in pulmonary pathophysiology. Chest. 128(Suppl): 592S–594S. 2005. View Article : Google Scholar : PubMed/NCBI

13 

Tuder RM, Chacon M, Alger L, Wang J, Taraseviciene-Stewart L, Kasahara Y, et al: Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J Pathol. 195:367–374. 2001. View Article : Google Scholar

14 

Yan J, Shen Y, Wang Y and Li BB: Increased expression of hypoxia inducible factor-1α in proliferating neointimal lesions in a rat model of pulmonary arterial hypertension. Am J Med Sci. 345:121–128. 2013.

15 

Archer SL, Gomberg-Maitland M, Maitland ML, Rich S, Garcia JG and Weir EK: Mitochondrial metabolism, redox signaling, and fusion: a mitochondria-ROS-HIF-1alpha-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer. Am J Physiol Heart Circ Physiol. 294:H570–H578. 2008. View Article : Google Scholar

16 

Déry MA, Michaud MD and Richard DE: Hypoxia-inducible factor 1: regulation by hypoxic and non-hypoxic activators. Int J Biochem Cell Biol. 37:535–540. 2005.PubMed/NCBI

17 

Bonello S, Zähringer C, BelAiba RS, Djordjevic T, Hess J, Michiels C, et al: Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site. Arterioscler Thromb Vasc Biol. 27:755–761. 2007. View Article : Google Scholar : PubMed/NCBI

18 

McMurtry MS, Archer SL, Altieri DC, et al: Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertention. J Clin Invest. 115:1479–1491. 2005. View Article : Google Scholar

19 

Stenmark KR, Meyrick B, Galie N, Mooi WJ and McMurtry IF: Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol. 297:L1013–L1032. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Sakao S, Tatsumi K and Voelkel NF: Reversible or irreversible remodeling in pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 43:629–634. 2010. View Article : Google Scholar : PubMed/NCBI

21 

Okada K, Tanaka Y, Bernstein M, Zhang W, Patterson GA and Botney MD: Pulmonary hemodynamics modify the rat pulmonary artery response to injury. A neointimal model of pulmonary hypertension. Am J Pathol. 151:1019–1025. 1997.PubMed/NCBI

22 

Nishimura T, Vaszar LT, Faul JL, Zhao G, Berry GJ, Shi L, et al: Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation. 108:1640–1645. 2003. View Article : Google Scholar : PubMed/NCBI

23 

Faul JL, Nishimura T, Berry GJ, Benson GV, Pearl RG and Kao PN: Triptolide attenuates pulmonary arterial hypertension and neointimal formation in rats. Am J Respir Crit Care Med. 162:2252–2258. 2000. View Article : Google Scholar : PubMed/NCBI

24 

Madhok BM, Yeluri S, Perry SL, Hughes TA and Jayne DG: Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells. Br J Cancer. 102:1746–1752. 2010. View Article : Google Scholar : PubMed/NCBI

25 

Bowers R, Cool C, Murphy RC, Tuder RM, Hopken MW, Flores SC, et al: Oxidative stress in severe pulmonary hypertension. Am J Respir Crit Care Med. 169:764–769. 2004. View Article : Google Scholar : PubMed/NCBI

26 

Bonnet S, Michelakis ED, Porter CJ, Andrade-Navarro MA, Thébaud B, Haromy A, et al: An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension. Circulation. 113:2630–2641. 2006. View Article : Google Scholar

27 

Fijalkowska I, Xu W, Comhair SAA, Janocha AJ, Mavrakis LA, Krishnamachary B, et al: Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells. Am J Pathol. 176:1130–1138. 2010. View Article : Google Scholar : PubMed/NCBI

28 

Dorfmüller P, Chaumais MC, Giannakouli M, Durand-Gasselin I, Raymond N, Fadel E, et al: Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension. Respir Res. 12:1192011.

29 

Xu D, Guo H, Xu X, Lu Z, Fassett J, Hu X, et al: Exacerbated pulmonary arterial hypertension and right ventricular hypertrophy in animals with loss of function of extracellular superoxide dismutase. Hypertension. 58:303–309. 2011. View Article : Google Scholar

30 

Brüne B and Zhou J: Nitric oxide and superoxide: interference with hypoxic signaling. Cardiovasc Res. 75:275–282. 2007.PubMed/NCBI

31 

Van Rheen Z, Fattman C, Domarski S, Majka S, Klemm D, Stenmark KR, et al: Lung extracellular superoxide dismutase overexpression lessens bleomycin-induced pulmonary hypertension and vascular remodeling. Am J Respir Cell Mol Biol. 44:500–508. 2011.

32 

BelAiba RS, Djordjevic T, Bonello S, Flügel D, Hess J, Kietzmann T, et al: Redox-sensitive regulation of the HIF pathway under non-hypoxic conditions in pulmonary artery smooth muscle cells. Biol Chem. 385:249–257. 2004. View Article : Google Scholar : PubMed/NCBI

33 

Görlach A, Diebold I, Schini-Kerth VB, Berchner-Pfannschmidt U, Roth U, Brandes RP, et al: Thrombin activates the hypoxia-inducible factor-1 signaling pathway in vascular smooth muscle cells: Role of the p22(phox)-containing NADPH oxidase. Circ Res. 89:47–54. 2001.PubMed/NCBI

34 

Dahal BK, Kosanovic D, Kaulen C, Cornitescu T, Savai R, Hoffmann J, et al: Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats. Respir Res. 12:602011. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Li B, Yan J, Shen Y, Liu Y and Ma Z: Dichloroacetate prevents but not reverses the formation of neointimal lesions in a rat model of severe pulmonary arterial hypertension. Mol Med Rep 10: 2144-2152, 2014.
APA
Li, B., Yan, J., Shen, Y., Liu, Y., & Ma, Z. (2014). Dichloroacetate prevents but not reverses the formation of neointimal lesions in a rat model of severe pulmonary arterial hypertension. Molecular Medicine Reports, 10, 2144-2152. https://doi.org/10.3892/mmr.2014.2432
MLA
Li, B., Yan, J., Shen, Y., Liu, Y., Ma, Z."Dichloroacetate prevents but not reverses the formation of neointimal lesions in a rat model of severe pulmonary arterial hypertension". Molecular Medicine Reports 10.4 (2014): 2144-2152.
Chicago
Li, B., Yan, J., Shen, Y., Liu, Y., Ma, Z."Dichloroacetate prevents but not reverses the formation of neointimal lesions in a rat model of severe pulmonary arterial hypertension". Molecular Medicine Reports 10, no. 4 (2014): 2144-2152. https://doi.org/10.3892/mmr.2014.2432
Copy and paste a formatted citation
x
Spandidos Publications style
Li B, Yan J, Shen Y, Liu Y and Ma Z: Dichloroacetate prevents but not reverses the formation of neointimal lesions in a rat model of severe pulmonary arterial hypertension. Mol Med Rep 10: 2144-2152, 2014.
APA
Li, B., Yan, J., Shen, Y., Liu, Y., & Ma, Z. (2014). Dichloroacetate prevents but not reverses the formation of neointimal lesions in a rat model of severe pulmonary arterial hypertension. Molecular Medicine Reports, 10, 2144-2152. https://doi.org/10.3892/mmr.2014.2432
MLA
Li, B., Yan, J., Shen, Y., Liu, Y., Ma, Z."Dichloroacetate prevents but not reverses the formation of neointimal lesions in a rat model of severe pulmonary arterial hypertension". Molecular Medicine Reports 10.4 (2014): 2144-2152.
Chicago
Li, B., Yan, J., Shen, Y., Liu, Y., Ma, Z."Dichloroacetate prevents but not reverses the formation of neointimal lesions in a rat model of severe pulmonary arterial hypertension". Molecular Medicine Reports 10, no. 4 (2014): 2144-2152. https://doi.org/10.3892/mmr.2014.2432
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team