Ceramides and other sphingolipids as drivers of cardiovascular disease

Abstract

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.

© 2021. Springer Nature Limited.

Figures

Fig. 1 ∣. Pathways controlling ceramide levels in the cardiovascular system.

Schematic depiction of the major pathways controlling ceramide levels in the heart and vascular endothelium: de novo synthesis, hydrolysis of complex sphingolipids (for example, sphingomyelin hydrolysis) and the salvage pathway. 3KSR, 3-ketosphinganine reductase; CDase, ceramidase; CERS, ceramide synthase; DES1, dihydroceramide desaturase 1; SK, sphingosine kinase; SMase, sphingomyelinase; SMS, sphingomyelin synthase; SPT, serine palmitoyltransferase.

Fig. 2 ∣. Ceramide-induced endothelial cell dysfunction.

Endothelial cell (EC) dysfunction is an impairment of the vascular endothelium to regulate vascular homeostasis, mainly owing to the loss of nitric oxide (NO) bioavailability. Ceramides have been shown to decrease NO production by increasing the production of reactive oxygen species (ROS) and by activating protein phosphatase 2A (PP2A). The latter effect is as a result of the capacity of ceramides to dissociate the inhibitor 2 of PP2A (I2PP2A) from the PP2A, liberating the enzyme to act on cellular substrates, including endothelial nitric oxide synthase (eNOS).

Fig. 3 ∣. Types of heart failure and the contribution of ceramides.

Heart failure (HF) with reduced ejection fraction (HFrEF) can be caused by ischaemic injury, such as myocardial infarction, and is characterized by dilated ventricles, apoptosis and replacement fibrosis. Ceramides can contribute to the development of atherosclerosis and ischaemic injury and also to cardiomyocyte apoptosis after myocardial infarction has occurred. HF with preserved ejection fraction (HFpEF) is caused by chronic systemic inflammation, often in the context of diabetes mellitus, hypertension, obesity and lipotoxicity, and is characterized by constricted ventricles and interstitial fibrosis. Ceramides are also associated with risk factors for the development of HFpEF and non-ischaemic HFrEF.

Fig. 4 ∣. Mechanisms linking ceramides to heart failure.

Ceramides produced either de novo or by sphingomyelin (SM) hydrolysis by sphingomyelinase (SMase) have been implicated in several actions in cardiomyocytes that could contribute to heart failure. Through actions in mitochondrial membranes, ceramides alter cellular energetics, induce reactive oxygen species (ROS) formation and promote cytochrome c release to initiate apoptosis. Some researchers have speculated that upregulation of anti-apoptotic proteins, such as B cell lymphoma 2 (BCL-2), could minimize this action in patients with heart failure with preserved ejection fraction (HFpEF). Ceramides have also been implicated in profibrotic pathways, such as the activation of cAMP-responsive elementbinding protein 3-like protein 1 (CREB3L1) to promote collagen deposition. FAT, fatty acid translocase (also known as platelet glycoprotein 4); HFrEF, heart failure with reduced ejection fraction; TNF, tumour necrosis factor.