Ceramides and other sphingolipids as drivers of cardiovascular disease

Increases in calorie consumption and sedentary lifestyles are fuelling a global pandemic of cardiometabolic diseases, including coronary artery disease, diabetes mellitus, cardiomyopathy and heart failure. These lifestyle factors, when combined with genetic predispositions, increase the levels of circulating lipids, which can accumulate in non-adipose tissues, including blood vessel walls and the heart. The metabolism of these lipids produces bioactive intermediates that disrupt cellular function and survival. A compelling body of evidence suggests that sphingolipids, such as ceramides, account for much of the tissue damage in these cardiometabolic diseases. In humans, serum ceramide levels are proving to be accurate biomarkers of adverse cardiovascular disease outcomes. In mice and rats, pharmacological inhibition or depletion of enzymes driving de novo ceramide synthesis prevents the development of diabetes, atherosclerosis, hypertension and heart failure. In cultured cells and isolated tissues, ceramides perturb mitochondrial function, block fuel usage, disrupt vasodilatation and promote apoptosis. In this Review, we discuss the body of literature suggesting that ceramides are drivers — and not merely passengers — on the road to cardiovascular disease. Moreover, we explore the feasibility of therapeutic strategies to lower ceramide levels to improve cardiovascular health. The metabolism of lipids accumulated in blood vessel walls and the heart produces sphingolipids, such as ceramides, which are associated with the development of diabetes mellitus, atherosclerosis, hypertension and heart failure. In this Review, the authors discuss ceramides as drivers of cardiovascular disease and therapeutic strategies to lower plasma and cardiac levels of ceramides. Key points Ceramides have been shown to accumulate in many tissues, including blood vessels and the heart, in individuals with cardiovascular disease (such as hypertension, heart failure and atherosclerosis). Serum ceramide levels are measured clinically as prognostic indicators of major adverse cardiovascular events. Inhibiting ceramide biosynthesis in mice and rats prevents the development of hypertension, atherosclerosis, diabetes mellitus and heart failure. Ceramides have pleiotropic actions that are relevant to metabolic disease, including inhibiting nitric oxide synthase, decreasing insulin sensitivity, altering mitochondrial bioenergetics, and inducing apoptosis and fibrosis. Several enzymes that c