The Dark Side of Sphingolipids: Searching for Potential Cardiovascular Biomarkers

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death and illness in Europe and worldwide, responsible for a staggering 47% of deaths in Europe. Over the past few years, there has been increasing evidence pointing to bioactive sphingolipids as drivers of CVDs. Among them, most studies place emphasis on the cardiovascular effect of ceramides and sphingosine-1-phosphate (S1P), reporting correlation between their aberrant expression and CVD risk factors. In experimental in vivo models, pharmacological inhibition of de novo ceramide synthesis averts the development of diabetes, atherosclerosis, hypertension and heart failure. In humans, levels of circulating sphingolipids have been suggested as prognostic indicators for a broad spectrum of diseases. This article provides a comprehensive review of sphingolipids' contribution to cardiovascular, cerebrovascular and metabolic diseases, focusing on the latest experimental and clinical findings. Cumulatively, these studies indicate that monitoring sphingolipid level alterations could allow for better assessment of cardiovascular disease progression and/or severity, and also suggest them as a potential target for future therapeutic intervention. Some approaches may include the down-regulation of specific sphingolipid species levels in the circulation, by inhibiting critical enzymes that catalyze ceramide metabolism, such as ceramidases, sphingomyelinases and sphingosine kinases. Therefore, manipulation of the sphingolipid pathway may be a promising strategy for the treatment of cardio- and cerebrovascular diseases.

Keywords: cardiovascular diseases; ceramides; cerebrovascular diseases; sphingolipids; sphingosine-1-phosphate.

Figure 1

Metabolism and structure of sphingolipids and their implication in cardio- and cerebrovascular diseases. Sphingolipid metabolism and structure are illustrated inside the cell. Ceramide is the heart of the sphingolipid metabolic pathway. Ceramide can be synthesized through several steps: (i) de novo synthesis pathway starting from l-serine and palmitoyl-CoA (red); (ii) SMase pathway, through hydrolysis of sphingomyelin (yellow); (iii) salvage pathway, long-chain sphingoid bases are reused to form ceramide through the action of ceramide synthase (green); (iv) or through hydrolysis of glycosphingolipids and sulfatites (azure). Ceramide can also be synthesized from ceramide-1-phosphate through the action of ceramide-1-phosphate phosphatase (blue). The main cardiovascular diseases and risk factors in which sphingolipids may be used as biomarkers are summarized outside the cell. Abbreviations: serine palmitoyl-CoA-acyltransferase (SPT), 3-ketosphinganine reductase (KSR), (dihydro)-ceramide synthase (CerS), ceramide desaturase (DES), ceramide kinase (CK), glucosylceramide synthase (GCS), glucosyl ceramidase (GCase), ceramidase (CDase), sphingosine-1-phosphate lyase (S1P lyase), sphingosine kinase (SK), sphingosine 1-phosphate phosphatase (S1PPase), sphingomyelin (SM) synthase (SMS), sphingomyelinase (SMase).