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O-acylated heparin derivatives with low anticoagulant activity decrease proliferation and increase alpha-smooth
T Bârzu1, A Desmoulière, J M Herbert
1Centre Choay, Gentilly, France.
European Journal of Pharmacology
|August 25, 1992
Summary
Modified heparin fragments show enhanced antiproliferative effects on smooth muscle cells without increasing anticoagulant activity. This modification also reverses smooth muscle cell de-differentiation, offering potential therapeutic applications.
Area of Science:
- Biochemistry
- Pharmacology
- Cell Biology
Background:
- Glycosaminoglycans, like heparin, have diverse biological activities.
- Smooth muscle cell proliferation and de-differentiation contribute to vascular diseases.
Purpose of the Study:
- To investigate the antiproliferative and cell-modulating effects of selectively O-acylated heparin fragments.
- To assess the impact of O-acylation on anticoagulant activity.
Main Methods:
- Preparation of O-acylated heparin fragments (butyrylation, hexanoylation).
- In vitro testing of anticoagulant activity.
- Assessment of antiproliferative effects on rat and rabbit smooth muscle cells.
- Evaluation of smooth muscle cell de-differentiation markers (alpha-smooth muscle actin expression).
Main Results:
- O-acylation significantly increased antiproliferative potency of heparin fragments (IC50 values of 1-2 µg/ml) compared to the starting compound (31 µg/ml).
- Anticoagulant activity remained low and did not increase with O-acylation.
- Antiproliferative activity correlated with the degree of O-acylation.
- O-acylated derivatives effectively reversed smooth muscle cell de-differentiation, indicated by increased alpha-smooth muscle actin expression.
Conclusions:
- Selective O-acylation of heparin fragments enhances antiproliferative effects and reverses smooth muscle cell de-differentiation without augmenting anticoagulant properties.
- These modified heparin fragments represent promising candidates for therapeutic interventions in vascular conditions characterized by smooth muscle cell proliferation.