Cardiovascular disease, particularly atherosclerosis, is a major cause of concern as it is the primary cause of death today. Atherosclerosis is an inflammatory disease that involves lipid accumulation, as well as proliferation and inflammation of vascular smooth muscle cells. Our studies further our understanding of the role of lipid regulation in vascular smooth muscle cells.

Diglycerides, phospholipid-derived second messengers, regulate PKC-dependent signaling cascades. There are two distinct species that exist, ester-linked and ether-linked, that determine the physiological outcome of the cell. Our studies demonstrate that ester-linked diacylglycerol promotes PDGF-induced proliferation through activation of PKC&egr;-dependent MAPK/ERK growth signaling. On the other hand, ether-linked diglycerides inhibit mitogenesis through inhibition of PKC&egr;-dependent MAPK/ERK signaling and through inhibition PI3K/AKT signaling. These studies demonstrate two mechanisms, a PKC&egr;-dependent and -independent pathway, by which ether-linked diglycerides inhibit mitogenesis in vascular smooth muscle cells.

To further understand the role of vascular smooth muscle cell growth, we examined the sphingolipid enzyme, ceramide kinase, responsible for the conversion of ceramide to ceramide-1-phosphate. Ceramide has been shown to stimulate signaling pathways that lead to growth arrest and/or apoptosis, whereas ceramide-1-phosphate has been shown to stimulate proliferation and inflammation. Our studies demonstrate that vascular smooth muscle cells have a direct involvement in endotoxin-induced inflammation and proliferation that is dependent upon ceramide kinase activation and production of ceramide-1-phosphate. Altered sphingolipid flux may be a contributor to determine a cell’s fate between growth arrest and proliferation. These studies demonstrate a novel mechanism by which sphingolipid flux is shifted from proapoptotic ceramide to promitogenic ceramide-1-phosphate through endotoxin-induced toll-like receptor 4 activation.

Collectively, our studies reveal several mechanisms by which bioactive lipids may determine vascular smooth muscle cell flux to either proliferation or cell growth arrest. The ability of ether-linked diglycerides to induce growth arrest, without inducing apoptosis, may be of therapeutic value in stent development for angioplasty. In addition, the ability to regulate ceramide kinase may be an effective therapy through inhibition of C1P-induced inflammation associated with vascular diseases, such as atherosclerosis, as well as other inflammatory diseases, such as diabetes.