Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.
Nat Rev Cardiol. 2021 Oct;18(10):701-711. doi: 10.1038/s41569-021-00536-1. Epub 2021 Mar 26.
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.
卡路里摄入量的增加和久坐不动的生活方式正在助长心血管代谢疾病的全球大流行，包括冠状动脉疾病、糖尿病、心肌病和心力衰竭。这些生活方式因素与遗传易感性相结合，会增加循环脂质的水平，这些脂质可以在非脂肪组织中积累，包括血管壁和心脏。这些脂质的代谢会产生生物活性中间体，破坏细胞功能和存活。大量证据表明，鞘脂类物质，如神经酰胺，在这些心血管代谢疾病中导致了大量的组织损伤。在人类中，血清神经酰胺水平被证明是不良心血管疾病结局的准确生物标志物。在小鼠和大鼠中，抑制或耗尽驱动神经酰胺从头合成的酶的药物治疗可预防糖尿病、动脉粥样硬化、高血压和心力衰竭的发生。在培养的细胞和分离的组织中，神经酰胺会破坏线粒体功能、阻止燃料利用、破坏血管舒张并促进细胞凋亡。在这篇综述中，我们讨论了大量文献表明神经酰胺是心血管疾病发生的驱动因素，而不仅仅是被动参与者。此外，我们还探讨了降低神经酰胺水平以改善心血管健康的治疗策略的可行性。
