Secretory Zn2+-dependent Sphingomyelinase Activity in the Serum of Patients with Type 2 Diabetes is Elevated

Introduction Sphingomyelin located in the plasma membrane is hydrolyzed by enzyme-neutral, Mg ++ -dependent sphingomyelinase, whereas sphingomyelin located in endosomes and lysosomes is hydrolyzed by acid, Zn ++ -independent sphingomyelinase. In both cases, ceramide and phosphocholine are the products of sphingomyelin hydrolysis. Ceramide is recognized to be the second messenger on the sphingomyelin signaling pathway [ 1 ]. Different cell types, such as human and murine macrophages, human skin fibroblasts and human monocytes, have been shown to secrete Zn ++ -dependent acid sphingomyelinase, and the enzyme has been named secretory sphingomyelinase [ 4 ]. Secretory sphingomyelinase is also the product of the acid sphingomyelinase gene [ 4 ]. It has also been shown that human vascular endothelial cells are a very rich source of the enzyme. They secrete the enzyme both apically and basolaterally, thus contributing to serum and arterial wall sphingomyelinase. The acid sphingomyelinase secreted by the endothelial cells is partially Zn ++ -independent [ 2 ]. Two forms of acid sphingomyelinase have been shown to be present in the serum: Zn ++ -dependent and Zn ++ -independent [ 6 ] [ 7 ]. The secretory sphingomyelinase is claimed to play an important role in the development of atherosclerosis. Though the optimum pH for the enzyme is around 5, it hydrolyzes sphingomyelin present in atherogenic low density lipoproteins (LDL) at a neutral pH. Hydrolysis of sphingomyelin in this lipoprotein fraction results in its subendothelial aggregation [ 3 ] [ 5 ]. Aggregated LDL in turn, induce macrophage cell formation [ 8 ]. In the light of this role of the secretory sphingomyelinase, it seems important to recognize factors regulating the enzyme’s activity in the arterial bed. Inflammatory cytokines such as interleukin-1β and interferon-γ have been shown to increase secretion of the enzyme in vitro [ 2 ]. Serum enzyme activity increases considerably during acute systemic inflammation in mice [ 9 ]. The activities of the two enzymes have been shown to remain stable in serum of patients with metabolic bone disease [ 6 ]. In patients with hemophagocytic lymphohistiocytosis, the activity of Zn ++ -dependent sphingomyelinase was elevated 10-20-fold whereas the activity of Zn ++ -independent form of the enzyme was elevated only by around 2-fold [ 10 ]. Diabetes is a disease that accelerates atherosclerosis development. The aim of the present study was to examine the activity of secretory sphingomyelinase in the serum of patients with type 2 diabetes. Activity of the Zn ++ -dependent form of the enzyme was found to be markedly elevated in the patient group compared to control subjects.