Patients on chronic
hemodialysis (HD) are at high risk for developing
atherosclerosis and cardiovascular complications.
Heparanase, an
endoglycosidase that cleaves
heparan sulfate (HS) side chains of
proteoglycans, is involved in extracellular matrix degradation and, as such, may be involved in the atherosclerotic lesion progression. We hypothesize that
heparanase is elevated in HD patients, partly due to its release from primed circulating polymorphonuclear leukocytes (PMNLs), undergoing degranulation. Priming of PMNLs was assessed by levels of CD11b and the rate of
superoxide release.
Heparanase mRNA expression in PMNLs was determined by RT-PCR. PMNL and plasma levels of
heparanase were determined by immunoblotting, immunofluorescence, and flow cytometry analyses. The levels of soluble HS in plasma were measured by a competition ELISA. This study shows that PMNLs isolated from HD patients have higher
mRNA and
protein levels of
heparanase compared with normal control (NC) subjects and that
heparanase levels correlate positively with PMNL priming. Plasma levels of
heparanase were higher in HD patients than in NC subjects and were further elevated after the dialysis session. In addition,
heparanase expression inversely correlates with plasma HS levels. A pronounced expression of
heparanase was found in human atherosclerotic lesions. The increased
heparanase activity in the blood of HD patients results at least in part from the degranulation of primed PMNLs and may contribute to the acceleration of the atherosclerotic process. Our findings highlight primed PMNLs as a possible source for the increased
heparanase in HD patients, posing
heparanase as a new risk factor for cardiovascular complications and
atherosclerosis.