Favourable modulation of the inflammatory changes in hypercholesterolemic atherogenesis by a low-molecular-weight heparin derivative

Abstract

Background In the hypercholesterolemic state, the net result of combined oxidative and nitrosative stress is a pro-inflammatory phenotype that is manifested as increased adhesion molecule expression, enhanced leucocyte trafficking, and increased vascular permeability. The present work explores the inflammatory aspects of hypercholesterolemic atherogenesis, and also evaluates the role of a low-molecular-weight heparin derivative (LMWH), Certoparin, on a biochemical basis. Methods and results Two groups of male Wistar rats were fed an atherogenic diet (normal rat chow plus 4% cholesterol, 1% cholic acid and 0.5% thiouracil-CCT diet) for 2 weeks. While one was left untreated, the other was administered LMWH (300 μg/day/rat commencing on day 8 and continued for a week). Increased concentrations of plasma C-reactive protein and fibrinogen and cardiac TNF-α indicated severe inflammation in the atherogenic diet fed rats. In comparison, these biochemical indices of inflammation diminished significantly in the LMWH treated group ( p < 0.001). Significant depletion of thiols, along with accentuated activities of the glutathione metabolising was observed in the cardiac and hepatic tissues of the untreated atherogenic rats, indicating heightened oxidative response. Tissue damage was marked by elevated levels of plasma and tissue hexose, hexosamine, hexuronic acid and sialic acid, which were reversed towards normalcy on LMWH administration. The activities of lysosomal enzymes ( N-acetyl glucosaminidase, β-glucuronidase, β-galactosaminidase and cathepsin-D) showed a marked increase in the CCT-diet fed rats, while LMWH treated rats showed normal activities ( p < 0.001). The osmotic fragility test revealed that the untreated hyperlipidemic rat erythrocytes were significantly fragile at high salt concentrations, while the response was normalized in the LMWH treated group ( p < 0.05). Further, hypercholesterolemia induced downregulation of physiological nitric oxide levels was corrected upon treatment with heparin-derivative. Conclusion The results of this work highlight the inflammatory changes in atherogenic conditions and that the low-molecular-weight heparin derivative affords substantial protection.