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
Experimental and Therapeutic Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1792-0981 Online ISSN: 1792-1015
Journal Cover
July-2019 Volume 18 Issue 1

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
July-2019 Volume 18 Issue 1

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

Silencing PDK1 limits hypoxia‑induced pulmonary arterial hypertension in mice via the Akt/p70S6K signaling pathway

  • Authors:
    • Ruomin Di
    • Zhongzhou Yang
    • Peng Xu
    • Yingjia Xu
  • View Affiliations / Copyright

    Affiliations: Department of Cardiology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, P.R. China, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210061, P.R. China
  • Pages: 699-704
    |
    Published online on: May 29, 2019
       https://doi.org/10.3892/etm.2019.7627
  • 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 present study aimed to investigate the effect of phosphoinositide‑dependent protein kinase‑1 (PDK1) on hypoxia‑induced pulmonary arterial hypertension (PAH). A mouse model of hypoxia‑induced PAH was generated using normal or PDK1‑knockout mice. Histological analysis and hemodynamic evaluations were performed to identify the progression of PAH. The expression and phosphorylation of PDK1/protein kinase B (Akt) signaling pathway associated proteins were detected by western blot analysis. Increased lung vessel thickness, right ventricular (RV) systolic pressure (RVSP), RV hypertrophy index (RVHI) values [the RV weight-to-left ventricular (LV) plus septum (S) weight ratio] and PDK1 expression were observed in the hypoxia‑induced PAH model compared with the normal control. The phosphorylation of AktT308, proline‑rich Akt1 substrate 1 (PRAS40) and S6KT229 was also notably increased in the PAH model compared with the control. The changes of proteins were not observed in the hypoxia treated PDK1flox/+: Tie2-Cre mice. Similarly, the RVSP and RVHI values, and PDK1 expression were reduced in the hypoxia treated PDK1flox/+: Tie2-Cre mice to a level comparable with those in the control, suggesting that PDK1 partial knockout significantly limited hypoxia‑induced PAH. The results of the present study indicate that PDK1 is essential for hypoxia‑induced PAH through the PDK1/Akt/S6K signaling cascades.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

View References

1 

Sankhe S, Manousakidi S, Antigny F, Arthur Ataam J, Bentebbal S, Ruchon Y, Lecerf F, Sabourin J, Price L, Fadel E, et al: T-type Ca2+ channels elicit pro-proliferative and anti-apoptotic responses through impaired PP2A/Akt1 signaling in PASMCs from patients with pulmonary arterial hypertension. Biochim Biophys Acta. 1864:1631–1641. 2017. View Article : Google Scholar

2 

Humar R, Kiefer FN, Berns H, Resink TJ and Battegay EJ: Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J. 16:771–780. 2002. View Article : Google Scholar : PubMed/NCBI

3 

Xia H, Diebold D, Nho R, Perlman D, Kleidon J, Kahm J, Avdulov S, Peterson M, Nerva J, Bitterman P and Henke C: Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis. J Exp Med. 205:1659–1672. 2015. View Article : Google Scholar

4 

Lu Y, Azad N, Wang L, Iyer AK, Castranova V, Jiang BH and Rojanasakul Y: Phosphatidylinositol-3-kinase/akt regulates bleomycin-induced fibroblast proliferation and collagen production. Am J Respir Cell Mol Biol. 42:432–441. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Sato S, Fujita N and Tsuruo T: Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene. 21:1727–1738. 2002. View Article : Google Scholar : PubMed/NCBI

6 

Orlacchio A, Arciuch VA and Cristofano AD: PDK1-dependent activation of AGC kinases is an absolute requirement for AKT oncogenic activity. Cancer Res. 74 (Suppl 19):4776. 2014.

7 

Dupuy F, Tabariès S, Andrzejewski S, Dong Z, Blagih J, Annis MG, Omeroglu A, Gao D, Leung S, Amir E, et al: PDK1-dependent metabolic reprogramming dictates metastatic potential in breast cancer. Cell Metab. 22:577–589. 2015. View Article : Google Scholar : PubMed/NCBI

8 

Li W, Qian L, Lin J, Huang G, Hao N, Wei X, Wang W and Liang J: CD44 regulates prostate cancer proliferation, invasion and migration via PDK1 and PFKFB4. Oncotarget. 8:65143–65151. 2017.PubMed/NCBI

9 

Fang B, Zhu J, Wang Y, Geng F and Li G: MiR-454 inhibited cell proliferation of human glioblastoma cells by suppressing PDK1 expression. Biomed Pharmacother. 75:148–152. 2015. View Article : Google Scholar : PubMed/NCBI

10 

Liu Y, Yang K, Sun X, Fang P, Shi H, Xu J, Xie M and Li M: MiR-138 suppresses airway smooth muscle cell proliferation through the PI3K/AKT signaling pathway by targeting PDK1. Exp Lung Res. 41:363–369. 2015. View Article : Google Scholar : PubMed/NCBI

11 

Yu ZL, Wang JN, Wu XH, Xie HJ, Han Y, Guan YT, Qin Y and Jiang JM: Tanshinone IIA prevents rat basilar artery smooth muscle cells proliferation by inactivation of PDK1 during the development of hypertension. J Cardiovasc Pharmacol Ther. 20:563–571. 2015. View Article : Google Scholar : PubMed/NCBI

12 

Mora A, Davies AM, Bertrand L, Sharif I, Budas GR, Jovanović S, Mouton V, Kahn CR, Lucocq JM, Gray GA, et al: Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia. EMBO J. 22:4666–4676. 2003. View Article : Google Scholar : PubMed/NCBI

13 

Belgardt BF, Husch A, Rother E, Ernst MB, Wunderlich FT, Hampel B, Klöckener T, Alessi D, Kloppenburg P and Brüning JC: PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and-independent pathways in control of energy homeostasis and stress response. Cell Metab. 7:291–301. 2008. View Article : Google Scholar : PubMed/NCBI

14 

Papandreou I, Cairns RA, Fontana L, Lim AL and Denko NC: HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 3:187–197. 2006. View Article : Google Scholar : PubMed/NCBI

15 

Ciuclan L, Bonneau O, Hussey M, Duggan N, Holmes AM, Good R, Stringer R, Jones P, Morrell NW, Jarai G, et al: A novel murine model of severe pulmonary arterial hypertension. Am J Respir Crit Care Med. 184:1171–1182. 2011. View Article : Google Scholar : PubMed/NCBI

16 

Song Y, Coleman L, Shi J, Beppu H, Sato K, Walsh K, Loscalzo J and Zhang YY: Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice. Am J Physiol Heart Circ Physiol. 295:H677–H690. 2008. View Article : Google Scholar : PubMed/NCBI

17 

Song Y, Jones JE, Beppu H, Keaney JF Jr, Loscalzo J and Zhang YY: Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice. Circulation. 112:553–562. 2005. View Article : Google Scholar : PubMed/NCBI

18 

Wang J, Chu ES, Chen HY, Man K, Go MY, Huang XR, Lan HY, Sung JJ and Yu J: microRNA-29b prevents liver fibrosis by attenuating hepatic stellate cell activation and inducing apoptosis through targeting PI3K/AKT pathway. Oncotarget. 6:7325–7338. 2015.PubMed/NCBI

19 

Abdalla M, Sabbineni H, Prakash R, Ergul A, Fagan SC and Somanath PR: The Akt inhibitor, triciribine, ameliorates chronic hypoxia-induced vascular pruning and TGFβ-induced pulmonary fibrosis. Br J Pharmacol. 172:4173–4188. 2015. View Article : Google Scholar : PubMed/NCBI

20 

Larson-Casey JL, Murthy S, Ryan AJ and Carter AB: Modulation of the mevalonate pathway by akt regulates macrophage survival and development of pulmonary fibrosis. J Biol Chem. 289:36204–36219. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Tang H, Chen J, Drennan AR, Fraidenburg DR, Song S, Sysol JR, Smith KA, Machado RF, Makino A and Yuan JX: Akt/mTOR signaling contributes to the development of pulmonary arterial hypertension, in D27. Preclinical models of pulmonary hypertension: Novel targets and pathways. Am Thoracic Soc. 189:A55592014.

22 

Dai W, Xu X, Li S, Ma J, Shi Q, Guo S, Liu L, Guo W, Xu P, He Y, et al: SOX4 promotes proliferative signals by regulating glycolysis through AKT activation in melanoma cells. J Invest Dermatol. 137:2407–2416. 2017. View Article : Google Scholar : PubMed/NCBI

23 

Dong Y, Liang G, Yuan B, Yang C, Gao R and Zhou X: MALAT1 promotes the proliferation and metastasis of osteosarcoma cells by activating the PI3K/Akt pathway. Tumor Biol. 36:1477–1486. 2015. View Article : Google Scholar

24 

Allard D, Figg N, Bennett MR and Littlewood TD: Akt regulates the survival of vascular smooth muscle cells via inhibition of FoxO3a and GSK3. J Biol Chem. 283:19739–19747. 2008. View Article : Google Scholar : PubMed/NCBI

25 

Sato S, Fujita N and Tsuruo T: Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene. 21:1727–1738. 2002. View Article : Google Scholar : PubMed/NCBI

26 

Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ and Kim DH: Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol. 9:316–323. 2007. View Article : Google Scholar : PubMed/NCBI

27 

Cai CX, Buddha H, Castelino-Prabhu S, Zhang Z, Britton RS, Bacon BR and Neuschwander-Tetri BA: Activation of insulin-PI3K/Akt-p70S6K pathway in hepatic stellate cells contributes to fibrosis in nonalcoholic steatohepatitis. Dig Dis Sci. 62:968–978. 2017. View Article : Google Scholar : PubMed/NCBI

28 

Seufferlein T and Rozengurt E: Rapamycin inhibits constitutive p70s6k phosphorylation, cell proliferation, and colony formation in small cell lung cancer cells. Cancer Res. 56:3895–3897. 2004.

29 

Syed DN, Chamcheu JC, Khan MI, Sechi M, Lall RK, Adhami VM and Mukhtar H: Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: Findings from 3-D melanoma skin equivalents and computational modeling. Biochem Pharmacol. 89:349–360. 2014. View Article : Google Scholar : PubMed/NCBI

30 

Chai X, Chu H, Yang X, Meng Y, Shi P and Gou S: Metformin increases sensitivity of pancreatic cancer cells to gemcitabine by reducing CD133+ cell populations and suppressing ERK/P70S6K signaling. Scientific Reports. 5:144042015. View Article : Google Scholar : PubMed/NCBI

31 

Li G, Shan C, Liu L, Zhou T, Zhou J, Hu X, Chen Y, Cui H and Gao N: Tanshinone IIA inhibits HIF-1α and VEGF expression in breast cancer cells via mTOR/p70S6K/RPS6/4E-BP1 signaling pathway. PLoS One. 10:e01174402015. View Article : Google Scholar : PubMed/NCBI

32 

Conejo R, de Alvaro C, Benito M, Cuadrado A and Lorenzo M: Insulin restores differentiation of Ras-transformed C2C12 myoblasts by inducing NF-kappaB through an AKT/P70S6K/p38-MAPK pathway. Oncogene. 21:3739–3753. 2002. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Di R, Yang Z, Xu P and Xu Y: Silencing PDK1 limits hypoxia‑induced pulmonary arterial hypertension in mice via the Akt/p70S6K signaling pathway. Exp Ther Med 18: 699-704, 2019.
APA
Di, R., Yang, Z., Xu, P., & Xu, Y. (2019). Silencing PDK1 limits hypoxia‑induced pulmonary arterial hypertension in mice via the Akt/p70S6K signaling pathway. Experimental and Therapeutic Medicine, 18, 699-704. https://doi.org/10.3892/etm.2019.7627
MLA
Di, R., Yang, Z., Xu, P., Xu, Y."Silencing PDK1 limits hypoxia‑induced pulmonary arterial hypertension in mice via the Akt/p70S6K signaling pathway". Experimental and Therapeutic Medicine 18.1 (2019): 699-704.
Chicago
Di, R., Yang, Z., Xu, P., Xu, Y."Silencing PDK1 limits hypoxia‑induced pulmonary arterial hypertension in mice via the Akt/p70S6K signaling pathway". Experimental and Therapeutic Medicine 18, no. 1 (2019): 699-704. https://doi.org/10.3892/etm.2019.7627
Copy and paste a formatted citation
x
Spandidos Publications style
Di R, Yang Z, Xu P and Xu Y: Silencing PDK1 limits hypoxia‑induced pulmonary arterial hypertension in mice via the Akt/p70S6K signaling pathway. Exp Ther Med 18: 699-704, 2019.
APA
Di, R., Yang, Z., Xu, P., & Xu, Y. (2019). Silencing PDK1 limits hypoxia‑induced pulmonary arterial hypertension in mice via the Akt/p70S6K signaling pathway. Experimental and Therapeutic Medicine, 18, 699-704. https://doi.org/10.3892/etm.2019.7627
MLA
Di, R., Yang, Z., Xu, P., Xu, Y."Silencing PDK1 limits hypoxia‑induced pulmonary arterial hypertension in mice via the Akt/p70S6K signaling pathway". Experimental and Therapeutic Medicine 18.1 (2019): 699-704.
Chicago
Di, R., Yang, Z., Xu, P., Xu, Y."Silencing PDK1 limits hypoxia‑induced pulmonary arterial hypertension in mice via the Akt/p70S6K signaling pathway". Experimental and Therapeutic Medicine 18, no. 1 (2019): 699-704. https://doi.org/10.3892/etm.2019.7627
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