Thrombomodulin is upregulated in cardiomyocytes during cardiac hypertrophy and prevents the progression of contractile dysfunction.
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.


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.
Department of Internal Medicine, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan. heng@mail.ncku.edu.tw
Yi-Heng
YH
Li
Hsing-Chun
HC
Chung
Chawn-Yau
CY
Luo
Ting-Hsing
TH
Chao
Kou-Gi
KG
Shyu
Guey-Yueh
GY
Shi
Hua-Lin
HL
Wu
D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D018450:Disease Progression; D006801:Humans; D051379:Mice; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018180:Thrombomodulin / Q000096:biosynthesis* / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology*
D002316:Cardiotonic Agents; D018180:Thrombomodulin