Atherosclerosis is a pathophysiological mechanism underlying coronary artery disease (CAD). Atherosclerotic plaques are formed within the regions of disrupted endothelium and/or the arterial wall. Within the bloodstream, lipids attach to water-soluble lipoproteins named apolipoproteins. Lipoproteins containing apo-B, which are the major protein component of very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low-density lipoprotein (LDL), pass through the disrupted endothelium and are endocytosed by macrophages within the intimal layer of the arteries. Therefore, lipoproteins are oxidized, which induces leukocyte accumulation and the formation of foam cells. It has been shown that LDL aggregation promotes the accumulation of cholesteryl ester-rich lipid droplets in the human primary monocyte-derived macrophages, induces matrix metalloproteinase-7 secretion from macrophage foam cells, and activates T-cells in vitro (50). LDL aggregation susceptibility depends on the particle lipid composition, including higher concentrations of sphingomyelins and ceramides and may be decreased by diet or proprotein convertase subtilisin/kexin 9 (PCSK9) inhibition (50). Moreover, blood flow disturbance within atherosclerosis-susceptible regions promotes the rearrangement of the microenvironment of the arterial wall intima, with vascular smooth muscle cell migration, extracellular matrix remodeling, plaque growth, fibrous cap formation, and necrotic core formation with calcifications (51, 52). Interestingly, LDL aggregation susceptibility prognosticates cardiovascular death in patients with CAD, therefore it has been concluded that intimal LDL aggregation facilitates atherogenesis, inflammation, and plaque rupture by inducing foam cell formation and the secretion of matrix metalloproteinase-7, and by activating T-cells, which increases the risk of death (50). Therefore, the reduction of sphingolipid content in aggregation-prone LDL with diet or treatment with a PCSK9 inhibitor could be beneficial in reducing the risk of CAD (50). Another important predisposing factor for the development of atherosclerosis is the deposition of the mineral hydroxyapatite in the extracellular matrix and in the arterial smooth muscle cells, leading to arterial calcification, which in turn is associated with plaque rupture, and an increased risk of heart disease and stroke (53). The calcification process can affect both the inner (arterial intimal calcification; AIC) and the middle (arterial medial calcification; AMC) walls of the arteries. AIC is associated with the obstruction of the arteries and the rupture of the atherosclerotic plaque (54), whereas, AMC predisposes to vessel stiffness and the development of systolic hypertension and increased pulse wave velocity, consequently leading to diastolic dysfunction and heart failure (55). Yuan et al. (56) showed that endothelium-specific AC gene knockout mic (Asah1^fl/fl/EC^cre) with streptozotocin-induced diabetes significantly augmented the production and activation of NOD-like receptor pyrin domain 3 (NLRP3) inflammasomes in the coronary artery endothelial cells, as well as significantly higher expression of exosome markers auch as CD63 and alkaline phosphatase (ALP) in the coronary arterial wall and interleukin 1 beta (IL-1β) release of exosomes in comparison with wild-type (WT/WT) littermates. Moreover, Asah1^fl/fl/EC^cre mice trated with streptozotocin revealed significant thickening of the coronary arterial wall and lower expression of tight junction protein compared to WT/WT littermates (56). Additionally, it has been shown that smooth muscle-specific acid ceramidase (Ac) gene knockout mice (Asah1^fl/fl/SM^Cre) during hypercalcemia caused by high doses of vitamin D had more severe AMC in both the aorta and the coronary arteries as well as upregulation of osteopontin and RUNX2 (osteogenic markers) in the aortic and coronary arterial medial wall, and CD63, AnX2 (sEV markers) and ALP expression (mineralization marker) in the coronary arterial media in comparison with Asah1^fl/fl/SM^wt and WT/WT mice (57). In addition, the same researchers showed that high doses of vitamin D-induced hypercalcemia in Smpd1^trg/SM^cre mice with overexpressing the acid lysosomal sphingomyelinase (SMPD1) gene specific for aortic and coronary smooth muscle cells contributed to higher aortic and coronary AMC as well as increased expression of RUNX2 and osteopontin in the coronary and aortic media (58).

On the basis of the available studies, it can be hypothesized that sphingolipids play an important role in endothelial dysfunction and thus may promote the atherosclerotic processes.

S1P appears to have a twofold effect on the development of atherosclerosis depending on the receptors through which it acts (59) (Figure 2). The interaction of S1P with S1PR1 may have antiatherosclerotic effects by inhibiting macrophage apoptosis and endothelial inflammation via intracellular pathway dependent on the phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PI3K/Akt) (60). On the other hand, S1PR1 may have a positive effect on the development of atherosclerosis by activating pro-inflammatory endothelial factors such as: intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), as well as by facilitating the formation of neointima formation by increasing the level of interleukin 6 (IL-6), which stimulates the proliferation and migration of vascular smooth muscle cells (VSMCs) (61, 62). S1P interacting with S1PR2 may also have a pro-atherosclerotic effect by promoting the inflammatory response of endothelial cells due to the increased expression of pro-inflammatory factors such as tumor necrosis factor α (TNF-α), interleukin 1 (IL-1), stimulating endothelial dysfunction (63). However, the interaction of S1P with S1PR2 may also have antiatherosclerotic effects by inhibiting the proliferation and migration of smooth muscle cells via the Rac protein and delaying the neointima formation (64, 65). Skoura et al. (66) have shown that ApoE and S1PR2-deficient Apoe-/-S1pr2-/-mice show reduced development of western diet-induced atherosclerosis, present decreased fibrous tissue, collagen and lipid content, as well as decreased necrotic core within the atherosclerotic plaque and a reduced number of macrophages within the vessel wall in comparison with the Apoe-/-S1pr2 + / + controls. Therefore, the authors suggested that S1PR2 signaling regulates macrophage infiltration and inflammatory cytokine secretion, thereby promoting atherosclerosis (66). On the other hand, Guanbataar et al. showed that ApoE-deficient mice receiving a S1PR2 antagonist and fed on a western-type diet resulted in the reduction of atherosclerotic plaque development, and alleviated endothelial dysfunction as well as resulting in significantly decreased lipid deposition, macrophage accumulation, and the expression of inflammatory proteins within the aorta (67). Similarly, S1P by activating S1PR3 can also promote the development of atherosclerosis, as does S1PR1 by activating endothelial ICAM-1 and VCAM-1 and causing its dysfunction (68). But S1P/S1PR3 signaling may also have antiatherosclerotic effects by inhibiting neointima formation (69). This same authors shown that S1PR3 genetic deficiency significantly increased neointima formation in the mouse carotid artery ligation model (69).

Interestingly, the available data indicate that not only the interaction of S1P with its receptors, but also the enzymes leading to S1P synthesis, may play an important role in the pathogenesis of atherosclerosis. Ishimaru et al. revealed that SPHK2, but not SPHK1-deficient mice, developed larger atherosclerotic plaques in comparison with the control mice, with no influence on the plasma lipid profile (70). Moreover, the authors found that SPHK2 is responsible for autophagosome- and lysosome-mediated catabolism of the intracellular lipids, therefore SPHK2 has been suggested to be a novel target for the treatment of atherosclerosis (70). The above observations seem to be corroborated by Feuerborn et al. who showed that LDL receptor-deficient mice transplanted with bone marrow lacking SPKH2 have an increased concentration of S1P in the erythrocytes, plasma, and high-density lipoprotein (HDL), and a reduced development of atherosclerotic plaques with smaller necrotic cores within lesions (71). Potì et al. revealed that, in LDL receptor-deficient mice on a western high-cholesterol diet, lowering plasma S1P levels by treatment with SKI-II, a SPHK1 inhibitor, increased the development of atherosclerotic lesions, and increased the levels of TNF-α and the expression of endothelial adhesion molecules (soluble intercellular adhesion molecule-1, sICAM-1; soluble vascular cell adhesion molecule-1, sVCAM-1) (72).

Similar to the enzymes that influence S1P synthesis, sphingomyelinases, which play a role in the anabolic pathways leading to the formation of ceramides from sphingomyelin, appear to play an important role in the pathogenesis of atherosclerosis. For example, it was shown that neutral as well as acid sphingomyelinase, which are expressed in the intima of atherosclerotic arteries, promotes foam cell formation by the production of Cer in lipoproteins and the enhancement of LDL uptake and has the ability to induce cholesteryl ester accumulation in macrophages (73–75). Moreover, sphingomyelinase induces aggregation and fusion of LDL, which can be a potential mechanism responsible for the focal retention of extracellular lipids in the arterial wall (76, 77). Moreover, ceramides themselves exert a pro-atherosclerotic effect by inducing endothelial dysfunction. It has been shown that ceramides in endothelial cells generate the ROS production and activating protein phosphatase 2A (PP2A), and consequently reduce the activity of eNOS, thus impairing the production and bioavailability of NO (28) (Figure 2).

The activity of sphingomyelin synthases also plays an important role in the pathogenesis of atherosclerosis. In ApoE-deficient mice, the administration of an adenovirus containing sphingomyelin synthase 2 resulted in the increased development of atherosclerosis, and its overexpression is associated with an increased aortic inflammatory response, contributing to endothelial dysfunction and plaque instability (78, 79). In addition, the overexpression of sphingomyelin synthases 1 and 2 significantly decreased (high-density lipoprotein) HDL-sphingomyelin and HDL-cholesterol, and increased non-HDL-sphingomyelin, non-HDL-cholesterol, and apolipoprotein B concentrations, thus exerting a proatherogenic effect (80).

Moreover, the latest research also indicates the important role of sphingolipids in the process of arterial calcification, which is one of the main mechanisms leading to the development of atherosclerosis (53) (Figure 3). The research of Koka et al. conducted both in the primary cultures of the mouse carotid arterial endothelial cells as well as in the mouse model of hypercholesterolemia showed that acid sphingomyelinase and ceramidases related to the formation of the membrane raft were necessary for the activation of NRLP3 inflammasomes in the endothelial cells and further increased atherosclerosis associated with hypercholesterolemia (81).

Numerous experimental data indicate the beneficial effect of modulating sphingolipid system in the pharmacotherapy of atherosclerosis. Exogenous administration of fingolimod decreased the development of atherosclerosis in LDL receptor-deficient mice and ApoE-deficient mice (82, 83). Administration of KRP-203, a S1PR1 agonist, reduced the development of atherosclerosis in LDL receptor-deficient mice on a cholesterol-rich diet by modulating the lymphocyte and macrophage function and improving the endothelial barrier (84). In ApoE-deficient mice on a chow or high fat diet, inhibition of de novo ceramide synthesis by the administration of myriocin, an inhibitor of SPT, resulted in significantly decreased plasma concentration of sphingomyelin, Cer, and S1P, and a significant increase in plasma phosphatidylcholine levels with no significant change in the cholesterol and triglyceride plasma concentrations. Most interestingly, both in ApoE-deficient mice fed on a chow or high fat diet, the administration of myriocin resulted in a significantly reduced atherosclerotic lesion area (85). In other studies on ApoE-knockout mice fed on a western diet, treatment with myriocin decreased plasma concentrations of sphingomyelin, sphinganine, cholesterol, and triglyceride with a concomitant decrease in beta-very-low-density lipoprotein (beta-VLDL) and LDL cholesterol, an increase in HDL cholesterol, a significant reduction of arterial atherosclerosis development, a reduction in the lesion and macrophage area, and the inhibition of necrotic core formation (86, 87).

Clinical studies seem to confirm the important role of sphingolipids in the atherogenic process and in the pathogenesis of CAD. However, data on the concentration of non-HDL-bound S1P in patients with CAD were inconclusive, but they were consistent with the decreased concentration of HDL-bound S1P in this group of patients, suggesting that CAD is associated with an uptake in the disturbance of HDL for plasma S1P (88–90). Moreover, HDL-associated S1P concentrations showed negative correlation with the severity of CAD and distinguishes one-vessel disease from multi-vessel disease, and a low concentration of HDL-associated S1P was predictive for CAD advancement (89). The serum concentration of S1P has been shown to be more predictive of obstructive CAD in comparison with traditional risk factors, such as age, sex, a family history of CAD, diabetes mellitus, lipid profile, and hypertension (90). Nevertheless, patients with stable CAD have increased plasma concentrations of sphingolipids, for example: ceramides, sphingomyelins, sphinganine, and sphingosine (91, 92). In a study by Poss et al., the total C24:1-containing sphingolipids and/or total dihydroceramides, independent of the chain length, were most strongly associated with the occurrence of CAD (91). Higher levels of plasma Cer(d18:1/20:0), Cer(d18:1/22:0), and Cer(d18:1/24:0) were significantly associated with the presence of left anterior descending coronary artery (LAD) stenosis ≥50% (93). Also, a high ratio of Cer(d18:1/24:1) to Cer(d18:1/24:0) was shown to be associated with more severe coronary artery stenosis (94). Finally, Meeusen et al. revealed that increased plasma concentrations of Cer(16:0), Cer(18:0), and Cer(24:1) are independently associated with major adverse cardiovascular events in patients with and without CAD (95). Moreover, a recent meta-analysis has shown that higher plasma concentrations of Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1) were associated with major adverse cardiovascular events (96). Therefore, novel CAD predictive ceramide risk scores were proposed, which show superior performance in comparison with traditional cardiovascular risk markers (91, 93, 97–100). Hilvo et al. improved the previously proposed ceramide risk score (CERT1) and established CERT2, which is a ceramide-based and phospholipid-based risk score for predicting the residual CVD event risk, especially cardiovascular death, in patients with CAD (97). CERT2 has been shown to have superior prognostic efficacy over troponin T (TnT) and LDL cholesterol and is associated with biomarkers of inflammation, myocardial necrosis, myocardial dysfunction, renal dysfunction, and dyslipidemia (97, 101).

In addition, based on available clinical studies, it appears that Cer composition seems to influence the morphology and vulnerability of atherosclerotic plaque. In the ATHEROREMO-IVUS study, Cheng et al. (102) revealed that higher plasma concentrations of Cer(d18:1/16:0) and Cer(d18:1/24:0) were associated with higher necrotic core fractions and lactosylceramide (d18:1/18:0), and with a higher coronary lipid core burden index (LCBI) on near-infrared spectroscopy (NIRS). A higher Cer(d18:1/20:0)/Cer(d18:1/24:0) ratio was associated with a higher plaque burden and the presence of dense calcium (102). Pan et al. (103) performed Optical Coherence Tomography in patients with STEMI and correlated culprit lesion characteristics with plasma Cer concentrations. The authors revealed that lipid-rich plaque, plaque rupture, and thin-cap fibroatheroma were more prevalent, while calcification occurred less often in patients with a high plasma Cer concentration in comparison with individuals with lower plasma Cer levels (103). Patients with a high plasma Cer concentration had a longer lipid core length, a larger mean lipid arc, and a bigger lipid volume index, which positively correlated with plasma Cer(d18:1/16:0), Cer(d18:1/18:0), and Cer(d18:1/24:1), and a thinner fibrous cap thickness (negatively correlated with the abovementioned Cer species) when compared with the low plasma Cer group. Moreover, four Cer species which have previously been shown to have a strong predictive value for major adverse cardiovascular events [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:1), and Cer(d18:1/24:0)] were also predictors for thin-cap fibroatheroma (103).

The current treatment of choice for acute myocardial ischemia is based on the immediate restoration of blood flow using primary coronary intervention (PCI) or thrombolytic therapy. Paradoxically, such early and fast restoration of blood flow further increases the ischemia-induced myocardial injury, which is called myocardial ischemia/reperfusion injury (IRI) (104–106).

Numerous studies have revealed that ischemic hearts show an increase in Cer and S1P levels, therefore it can be concluded that sphingolipids are involved in the pathophysiology of IRI. However, considering the important role of ceramides in apoptosis of cardiomyocytes, researchers most often attribute an unfavorable effect on the myocardium to them, while S1P is considered a cardioprotective effect.

As mentioned above, Cer mediates the ischemia/reperfusion-induced apoptosis of cardiomyocytes (107, 108). In vitro studies on isolated rat hearts subjected to ischemia/reperfusion (I/R) have an increased myocardial level of Cer and S1P, and decreased levels of sphingomyelin and sphingosine (109–111). Moreover, it was found that in isolated rat hearts subjected to I/R, Cer was accumulated specifically in the mitochondria, but not in the microsomal fraction (112). The I/R group also had increased mitochondrial activity of neutral sphingomyelinase, which was decreased in rats treated with a sphingomyelinase inhibitor (D609), with no changes in the microsomal fraction in any group. Moreover, in isolated rat hearts subjected to I/R, the injection of D609 significantly reduced infarct size, myocardial ceramide concentration, and the ratio of active caspase 3/pro-caspase 3, as a marker of active apoptosis and ROS production (112). Additionally, ischemic pre-conditioning seems to partially prevent a reperfusion-induced increase in myocardial Cer concentrations (113).

Moreover, in vivo studies have shown that increased myocardial concentrations of ceramide due to I/R are probably associated with the reduced activity of ceramidase (111). A rat model of I/R revealed that the ischemic myocardium as well as the ischemic and reperfused myocardium have an increased concentration of Cer(16:0, 18:0, 18:1, 18:2, and 20:4) (108, 113). Additionally, it was revealed that I/R in mice increased the myocardial concentration of ceramide both in the infarct area and in the area at risk, with a concomitant increased expression of two subunits of the SPTLC1 and SPTLC2 in the area at risk, suggesting that I/R enhances the accumulation of ceramide via the activation of the de novo synthesis pathway (114). In turn, intraventricular administration of nanocarriers loaded with the SPT inhibitor myriocin at reperfusion significantly reduced the infarct size, decreased the inflammatory response in the area at risk, and reduced the myocardial reactive oxygen species production (114). Since myriocin also regulates cardiac metabolism and inflammatory responses after I/R injury, it has been proposed that myriocin might serve as a post-conditioning therapeutic tool (115).

Whereas Cer has a rather an adverse effect on the heart muscle, S1P protected the heart from I/R myocardial injury and is released together with adenosine during ischemic pre-conditioning and post-conditioning (116–118). Pre-conditioning or post-conditioning with S1P protected the isolated rat heart against I/R-induced myocardial injury (119–121). This is probably done via controlling the mitochondrial function and Akt/glycogen synthase kinase β (Gsk3β) phosphorylation (121). Moreover, S1P played a cardioprotective role in I/R also through the activation of the S1PR3- Ras homolog family member A/protein kinase D (RhoA/PKD) signaling cascade in S1P3 KO mouse cardiomyocytes (122). Moreover, pharmacological inhibition of S1P lyase prior to I/R in isolated murine hearts increased the myocardial levels of S1P, reduced the infarct size and enhanced hemodynamic recovery Moreover, pharmacological inhibition of S1P lyase prior to I/R in isolated murine hearts increased the myocardial levels of S1P, reduced the infarct size and enhanced hemodynamic recovery (123). On the other hand, studies on isolated mouse and rat hearts showed that ischemia decreased the myocardial activity of sphingosine kinase and activates S1P lyase, which leads to reduced myocardial levels of S1P (123, 124).

S1P can affect the myocardium during I/R through its receptors. Studies carried out on both mouse and rat hearts have shown that exogenously administered S1P and stimulation of the S1PR1 receptor, as well as activation of SPHK1, protect against hypoxia- and oxygen-glucose deprivation/reoxygenation-induced myocardial cell death, respectively (125–128). Furthermore, in mouse model of I/R, S1P reduced the myocardial infarction size, reduced inflammatory cell recruitment and apoptosis of cardiomyocytes, thus exerting cardioprotective effects against I/R injury, through the activation of S1PR3-mediated and nitric-oxide dependent pathways (129). Additionally, Means et al. showed that activation of both S1PR2 and S1PR3 receptors are involved in cardioprotection against I/R injury, since the knockout of either S1PR2 or S1PR3 alone does not influence the in vivo response to I/R injury, while the knockout of both receptors significantly increases the I/R injury-related infarct size (130). Recently, Zhang et al. (131) in the rat model of I/R showed that blockage of the S1PR2/S1PR3 receptors with specific antagonists increased IR-induced mortality and infarction size, induced conduction abnormalities, and decreased the fractional shortening and ejection fraction of LV. While pre-treatment with S1PR2 and S1PR3 agonists at least partially reversed those changes (131). Afterward, the interaction of S1P with its receptors activates intracellular pathways also having a cardioprotective effect against ischemia. It have been shown that two signaling pathways to be involved in the above process: the Survivor Activating Factor Enhancement (SAFE) and the Reperfusion Injury Salvage Kinase (RISK) pathways. The SAFE pathway is activated by ischemic conditioning and/or by reperfusion and promotes cell survival through the activation of TNF-α which therefore activates its receptor TNF-R2, leading to the Janus kinase/signal transducer and activator of transcription 3 pathway (JAK/STAT-3) (132). The RISK pathway is activated by reperfusion and has a cardioprotective effect through the activation of two independent cascades, i.e., the PI3K-Akt or mitogen-activated extracellular signal-regulated kinase (MAPK, MEK1/ERK1/ERK2) (132). Somers et al. (133) revealed that S1P administered at the time of reperfusion to isolated rat hearts subjected to I/R reduced the myocardial infarct size in wild type animals, but not in STAT-3 or TNF-deficient mice. Moreover, after reperfusion in wild type mice, the authors revealed increased nuclear levels of phosphorylated STAT-3, Akt, and FOXO1, which is a downstream target of the RISK pathway (133). Moreover, it has been shown that activation of STAT-3 is required for the S1P-induced reduction of the infarction area in I/R (134).

Although human studies regarding sphingolipid involvement in I/R are scarce, it has been shown that, in patients undergoing elective percutaneous coronary intervention, coronary sinus levels of S1P, sphingosine, and sphinganine were increased as soon as 1 min following transient ischemia and reperfusion (135).

Regarding the currently used nomenclature, acute coronary syndromes (ACS) include ST-segment elevation ACS. Most patients will develop ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation ACS (NSTE-ACS), including myocardial ischemia without cardiomyocyte necrosis (unstable angina) or non-ST-segment elevation myocardial infarction (NSTEMI) (106). From the pathophysiological point of view, myocardial infarction (MI) mostly results from atherosclerotic plaque rupture or erosion and in the vast majority of cases depends on the composition and vulnerability of the atherosclerotic plaque (51).

Based on the available data, it can be concluded that sphingolipids also play an important role in the pathogenesis of acute coronary syndrome and myocardial infarction. Moreover, the studies presented below reveal a rather unfavorable effect of Cer on the heart muscle and a definitely cardioprotective effect of S1P.

It has been shown that ceramides by their activity in mitochondrial membranes caused alter cellular energetics, generating ROS formation and initiating cytochrome C release to promote apoptosis through caspase 3 pathways (Figure 4) (28). Cer also play a profibrotic role, because they can active of cyclic adenosine monophosphate responsive element binding protein 3 like 1 (CREB3L1) pathway to promote collagen deposition consequently leading to the development of heart failure with reduced ejection fraction (HFrEF) as well as heart failure with preserved ejection fraction (HFpEF) (Figure 4) (28).

The adverse effects of Cer on the heart were reflected in in vivo experimental studies. Hadas et al. (136) have proven that, in Swiss Webster (CFW) mice 24 h after ligation of LAD, several genes involved in de novo synthesis of Cer were upregulated and myocardial concentrations of C16, C20, C20:1, and C24 ceramides were increased. Moreover, treatment with modified mRNA (modRNA) enhanced the activity of acid ceramidase and reduced hypoxia-induced cell death and resulted in a reduced inflammatory response, in improved cardiac function, in a smaller scar area, and in longer survival post infarction (136). In the reparative phase post MI induced by LAD ligation, C57BL/6 mice have significantly higher myocardial concentrations of Cer16:0, Cer24:1, ceramide-1-phosphates (Cer1P; 14:0, 18:1, 18:2, 18:3), dihydroceramide-1-phosphates (14:0, 16:0, 18:2, 20:4, 20:5), monohexosylceramides (20:0, 22:0, 24:0, and 24:1), dihexosylceramides (22:0, 24:1, 24:0), and lower myocardial concentrations of two dihydro sphingomyelins (38:4 and 40:0) in comparison with the sham-operated control group (137). Moreover, the MI group had higher expressions of Cer kinase (Cerk), as well as higher ratios of the Cer1P/Cer, which suggests that in the reparative phase post MI, the upregulated expression of Cerk may lead to enhanced conversion of Cer to Cer1P (137). In addition, myocardial concentrations of Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), and Cer(d18:1/24:0), as well as the expression of serine palmitoyl transferase-2 (the gene encoding a base subunit of SPT), ceramide synthase 6 (CerS6), and neutral sphingomyelinase (nSMase) were found to be significantly higher in Wistar rats with acute MI induced by LAD occlusion in comparison with the sham-operated control group (138).

As mentioned before, unlike Cer, S1P is assigned a rather cardioprotective role in the course of acut coronary syndrome and myocardial infarction. It has been shown that the beneficial effects of S1P on the heart can be exerted by its receptors, of which S1PR1 and S1PR3 are widespread, while S1PR2 expression is low in the myocardium (Figure 4). S1PR1 has been disclosed to act as a protector in ischemic myocardial injury since soothes inflammatory responses and stimulates the proliferation of repair macrophages as well as inhibits myocardial fibrosis via Akt/eNOS dependent pathway (59). Nevertheless, S1PR1 also affect negatively on the heart by aggravating arrhythmias (59). In turn, the interaction of S1P with S1PR2 and S1PR3 exerts a cardioprotective effect, mainly by maintaining the conduction of myocyte action potential by inducing connexin 43 (Cx43) phosphorylation and phosphorylation of serine/threonine protein kinase B (AKT) (59). Similarly, the available experimental studies show a beneficial effect of S1P on the heart muscle in the course of MI. In C57BL/6 mice, pharmacological elevation of circulating S1P attracted hematopoietic stem cells and promoted tissue regeneration within the infarct zone, thus leading to cardiac structural and functional improvement after myocardial infarction (139). The studies of Yang et al. revealed that S1P induced the autophagy of cardiomyocytes after MI through the inhibition of the mammalian target of rapamycin (mTOR) signaling pathway, preventing adverse remodeling following MI in Sprague-Dawley rats (140). Moreover, in rats, myocardial infarction reduced the plasma concentrations of S1P, dihydrosphingosine-1-phosphate, sphingosine, and dihydrosphingosine but increased the concentration of total Cer, with concomitant alteration in the sphingolipid levels in the erythrocytes and platelets (141).

Based on the available data, it can be concluded that clinical trials seem to confirm the experimental results. Recently Yao et al. has shown that the Cer(d18:1/24:1(15Z)/Cer(d18:1/24:0) ratio, Cer(d18:1/14:0), and Cer(d18:1/22:0) can be independent predictors of acute coronary syndrome in patients with chest pain and added to high-sensitive troponin and traditional factors to improve the diagnostics of ACS (142). Patients with acute coronary syndrome, including unstable angina (UA) and AMI, had significantly higher concentrations of ceramide and secretory acid sphingomyelinase in comparison with healthy controls and individuals with stable angina (103, 143). Interestingly, increased plasma concentrations of Cer was sustained until a day after percutaneous coronary intervention in UA or day 7 in AMI patients (143). In another study, patients with ACS have been shown to have higher plasma concentrations of Cer(d18:1/16:0), Cer(d18:1/24:0), lactosylceramide (d18:1/18:0), and the Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio in comparison with stable CAD (102). Recently, Burrello et al. revealed that patients with STEMI have significantly increased extracellular vesicle total content of Cer, dihydroceramides, and sphingomyelins in comparison with the controls and the prognostic ability of their levels was not inferior to troponin as a biomarker for AMI (144). The sphingolipid concentration within the extracellular vesicles (EV) was correlated to the peak level of high sensitive troponin and decreased 24 h post coronary artery reperfusion (144). Karagiannidis et al. evaluated patients with STEMI subjected to primary percutaneous coronary intervention and thrombus aspiration and revealed that higher ceramide C16:0 plasma concentrations were significantly correlated with larger aspirated thrombus volume, larger intracoronary thrombus burden, and poorer pre- and post-procedural thrombolysis in myocardial infarction (TIMI) flow; ceramides C24:0 and C24:1 were also associated with a larger intracoronary thrombus burden (145). Furthermore, plasma concentration of sphingomyelin, ceramide and glucosylceramide has been shown to correlate positively with high-sensitivity C-reactive protein, as a marker of inflammation in patients with myocardial infarction (146). Ceramides has also been proposed as a promising prognostic biomarker in patients with myocardial infarction. De Carvalho et al. proposed a 12-ceramide plasma signature which predicted cardiovascular death, MI, and stroke at 1 year in patients with acute MI (138). Cer (d18:0/16:0) and Cer (t18:0/12:0) and sphinganine have been shown to have high prognostic sensitivity and specificity for major adverse cardiovascular events for patients under 45 years of age with STEMI (147).

In addition, patients with STEMI have decreased plasma concentrations of S1P and sphinganine-1-phosphate, while the erythrocyte concentrations of S1P, sphingosine, sphinganine, sphinganine-1-phosphate were significantly increased on hospital admission and some of them were sustained for 2 years following infarction (148, 149). Moreover, in patients with myocardial infarction, the uninfected area of the myocardium presents a reduced S1P/Cer ratio (141). It has been shown that increased plasma concentrations of S1P correlated significantly with the occurrence of pre-infarction angina (150). Recently, Polzin et al. suggested that S1P may be responsible for the “Ang II receptor blockers (ARB)-myocardial infarction” paradox, which is a phenomenon in which ARB do not reduce the risk of myocardial infarction, despite effective blood pressure control (151). The authors revealed that patients treated for 3 months with ARB have a significantly lower plasma concentration of S1P in comparison with the patients treated with angiotensin converting enzyme inhibitors (ACEI) (151).