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Basic science: Cardiovascular disease basic research
e0146 Altered expression of ADAMTS-1 and its inhibitor in rats with chronic heart failure induced by adriamycin
  1. Li Jianqiang,
  2. Li Weimin,
  3. Li Yue,
  4. Zhao Jiyi,
  5. Kong Yihui,
  6. Guo Hong,
  7. Xue Jingyi,
  8. Sheng Li,
  9. Gong Yongtai,
  10. Xue Hongjie
  1. The First Affiliated Hospital of Harbin Medical University, Harbin, China

Abstract

Purpose The clinical progression of chronic heart failure (CHF) is largely determined by ventricular remodelling, which involves cellular and extracellular matrix disruption. A disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS-1) is known to regulate cell-cell and cell-matrix interactions, and may thereby influence cardiac structure. The present study was undertaken to investigate the expression of ADAMTS-1 and its endogenous inhibitor, tissue inhibitor of metalloproteinases-3 (TIMP-3), in rats with CHF.

Methods 60 healthy male Wistar rats were randomly divided into a control group (n=30) and a CHF group (n=30). Adriamycin was administered intraperitoneally (2.5 mg/kg each week) to rats in the CHF group for 6 weeks. Rats in the control group received saline in the same regimen with adriamycin treatment. Animals in both groups were observed for 4 weeks after the last injection for general appearance, behaviour, and mortality. Before and 10 weeks after initiating the study, body weight (BW), left ventricular weight (LVW), and LVW/BW were measured; left ventricular end diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF), and fractional shortening (FS) were assessed; and left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), and maximum rates of rise and fall of left ventricular pressure (±dp/dtmax) were recorded. 10 weeks after the study started, pathohistological and ultrastructural changes in ventricular tissue were examined by light and electron microscopy. Collagen volume fraction (CVF) and apoptotic index were analysed by Masson staining and TUNEL assay, respectively. Levels of ADAMTS-1, Syndecan-4, and TIMP-3 were evaluated using immunohistochemistry and western blot, respectively.

Results After the adriamycin treatment, BW in the CHF group was slowly increased, while LVW was quickly increased, resulting in a higher LVW/BW than that in the control group (p<0.01). Compared with the control group, LVEF, FS, LVSP, and ±dP/dtmax were reduced in the CHF group (p<0.05), whereas LVEDD and LVEDP were augmented (p<0.01). There was a significant increase in myolysis, fibrosis, and apoptosis in the CHF group (p<0.01). The protein expression of ADAMTS-1 and Syndecan-4 was dramatically up-regulated in the CHF group (p<0.01), and that of TIMP-3 was down-regulated compared to those in the control group (p<0.05). In addition, there was a positive correlation between the protein expression of ADAMTS-1 and LVEDD in both groups (r=0.804, p<0.01).

Conclusion Along with decreased TIMP-3, ADAMTS-1 is over-expressed in the ventricle of CHF rats and is associated with ventricular remodelling via cleaving the ectodomain of Syndecan-4. Therefore, ADAMTS-1 may provide a new therapeutic target in the prevention and treatment of ventricular remodelling in CHF.

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