Cardiovascular diseases are the leading cause of mortality worldwide and this has largely been driven by the increase in metabolic disease in recent decades. Metabolic disease alters metabolism, distribution, and profiles of sphingolipids in multiple organs and tissues; as such, sphingolipid metabolism and signaling have been vigorously studied as contributors to metabolic pathophysiology in various pathological outcomes of obesity, including cardiovascular disease. Much experimental evidence suggests that targeting sphingolipid metabolism may be advantageous in the context of cardiometabolic disease. The heart, however, is a structurally and functionally complex organ where bioactive sphingolipids have been shown not only to mediate pathological processes, but also to contribute to essential functions in cardiogenesis and cardiac function. Additionally, some sphingolipids are protective in the context of ischemia/reperfusion injury. In addition to mechanistic contributions, untargeted lipidomics approaches used in recent years have identified some specific circulating sphingolipids as novel biomarkers in the context of cardiovascular disease. In this review, we summarize recent literature on both deleterious and beneficial contributions of sphingolipids to cardiogenesis and myocardial function as well as recent identification of novel sphingolipid biomarkers for cardiovascular disease risk prediction and diagnosis.
Cardiomyopathy is the leading cause of mortality worldwide. While the causes of cardiomyopathy continue to be elucidated, current evidence suggests that aberrant bioactive lipid signaling plays a crucial role as a component of cardiac pathophysiology. Sphingolipids have been implicated in the pathophysiology of cardiovascular disease, as they regulate numerous cellular processes that occur in primary and secondary cardiomyopathies. Experimental evidence gathered over the last few decades from both in vitro and in vivo model systems indicates that inhibitors of sphingolipid synthesis attenuate a variety of cardiomyopathic symptoms. In this review, we focus on various cardiomyopathies in which sphingolipids have been implicated and the potential therapeutic benefits that could be gained by targeting sphingolipid metabolism.
Human umbilical cord blood is a rich source of hematopoietic stem and progenitor cells. CD34+ cells in umbilical cord blood are more primitive than those in peripheral blood or bone marrow, and can proliferate at a high rate and differentiate into multiple cell types. In this protocol, a dependable method is described for the isolation of fetal CD34+ cells from umbilical cord blood and expanding these cells in culture. The cells can then be in vitro differentiated along an erythroid pathway, while simultaneously performing knockdown of a gene of choice. The use of lentiviral vectors that express small hairpin RNA (shRNA) is an efficient method to downregulate genes. Flow cytometric analyses are used to enrich for erythroid cells. Using these methods, one can generate in vitro differentiated cells to use for quantitative reverse transcriptase PCR and other purposes.
Rationale: Heart failure caused by ischemic cardiomyopathy is the leading cause of death and disability in the USA and world, accounting for 10 million deaths in 2016. Sphingolipids including ceramides and sphingosine-1-phosphate have been demonstrated to play roles in myocardial injury. In general, these lipids are synthesized from serine palmitoyltransferase (SPT) derived using serine and palmitoyl-CoA. While the standard SPT enzyme exists as a heterodimer of two subunits, Sptlc1 and Sptlc2, a new subunit was recently discovered, Sptlc3, which enables the SPT complex to use myristoyl-CoA, thereby synthesizing a previously underappreciated group of atypical sphingolipids. We previously demonstrated that these atypical lipids are a major component of myocardial sphingolipid pools. Furthermore, in contrast to canonical sphingolipids, the atypical lipids promote cardiomyocyte apoptosis. Therefore, the goal of this research is to determine the contribution of these novel lipids to cardiomyocyte apoptosis and therefore whether they may contribute to ischemic injury. Objectives: To determine the contribution of Sptlc3 and atypical sphingolipids to cardiomyocyte apoptosis and ischemic injury and to assess the potential relevance of Sptlc3 to human HF. Methods: Murine primary cardiac fibroblasts and cardiomyocytes were isolated and subject to ischemic induction. Following this, cells were analyzed with TUNEL staining, lipidomic analysis or treatment with a Sptlc3 mimetic. Results: Ischemic cells show significantly increased Sptlc3 expression, non-canonical sphingolipids in the sphingolipid pool and apoptotic cells as compared to their controls. The cells treated with the Sptlc3 mimetic show apoptotic and a non-canonical autophagic pathway being induced in cells. Conclusions: We have identified a novel class of sphingolipids enriched in myocardium of mice with cardiomyopathies. Furthermore, the enzyme that produces these, Sptlc3, is robustly increased in human heart failure. Because the Sptlc3-derived lipids promoted cardiomyocyte apoptosis, we propose that Sptlc3 may mediate myocardial injury in ischemia.
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