Journal of Cardiac Failure
Volume 16, Issue 12 , Pages 980-990, December 2010

Thrombomodulin is Upregulated in Cardiomyocytes During Cardiac Hypertrophy and Prevents the Progression of Contractile Dysfunction

  • Yi-Heng Li, MD, PhD

      Affiliations

    • Department of Internal Medicine, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan
    • Cardiovascular Research Center, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan
    • Corresponding Author InformationReprint requests: Yi-Heng Li, MD, PhD, Department of Internal Medicine, National Cheng Kung University Hospital, 138 Sheng Li Road, Tainan 704, Taiwan. Tel: +886-6-2353535 ext 2392; Fax: +886-6-2753834.
    • ,
  • Hsing-Chun Chung, MS

      Affiliations

    • Department of Internal Medicine, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan
    • Cardiovascular Research Center, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan
    • ,
  • Chawn-Yau Luo, MD

      Affiliations

    • Cardiovascular Research Center, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan
    • Department of Surgery, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan
    • ,
  • Ting-Hsing Chao, MD

      Affiliations

    • Department of Internal Medicine, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan
    • Cardiovascular Research Center, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan
    • ,
  • Kou-Gi Shyu, MD, PhD

      Affiliations

    • Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
    • ,
  • Guey-Yueh Shi, PhD

      Affiliations

    • Cardiovascular Research Center, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan
    • Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    • ,
  • Hua-Lin Wu, PhD

      Affiliations

    • Cardiovascular Research Center, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan
    • Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Received 12 February 2010; received in revised form 13 May 2010; accepted 16 June 2010. published online 20 July 2010.

Abstract 

Background

Cardiac hypertrophy is a common response to pressure overload and leads to left ventricular (LV) dysfunction. Thrombomodulin (TM), an endothelial anticoagulant protein, was found to have direct effects on cellular proliferation and inflammation. We examined the TM expression in cardiomyocytes during cardiac hypertrophy and investigated its physiological significance.

Methods and Results

TM expression was evaluated in cardiomyocytes from hearts of mice that underwent transverse aortic constriction (TAC). The effects of recombinant TM protein on cardiomyocytes apoptosis and related signaling pathways were examined. Recombinant TM protein was administered continuously in mice that underwent TAC, and serial LV function was determined. There was significant TM expression in cardiomyocytes during cardiac hypertrophy elicited by TAC in mice. TM treatment decreased doxorubicin-induced apoptosis of cardiomyocytes and increased the Bcl-2/Bax ratio. It also increased cardiomyocytes hypertrophy, expression of atrial natriuretic peptide, and significantly activated the extracellular signal–regulated kinase 1/2 (ERK1/2) and the phosphatidylinositol-3-kinase (PI3-K)/protein kinase B (Akt) signaling pathways in cardiomyocytes. Continuous TM supply after TAC prevented the progression of LV contractile dysfunction in mice.

Conclusions

TM treatment decreased cardiomyocyte apoptosis and maintained LV contractile function in response to pressure overload.

Key Words: Cardiac hypertrophy, heart failure, thrombomodulin

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 This work was supported by grants NSC96-2314-B-006-063-MY2, NSC98-2314-B-006-050-MY2, and NSC 96-2752-B-006-005-PAE from the National Science Council, Taipei, Taiwan and grants NCKUH-9701006 and 9802009 from the National Cheng Kung University Hospital, Tainan, Taiwan.

 See page 989 for disclosure information.

PII: S1071-9164(10)00713-X

doi:10.1016/j.cardfail.2010.06.415

Journal of Cardiac Failure
Volume 16, Issue 12 , Pages 980-990, December 2010

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