sphingosine-1-phosphate and Coronary-Disease

Cardiovascular diseases (CVDs) are the leading cause of death globally and the number of cardiovascular patients, which is estimated to be over 30 million in 2018, represent a challenging issue for the healthcare systems worldwide. Therefore, the identification of novel molecular targets to develop new treatments is an ongoing challenge for the scientific community. In this context, sphingolipids (SLs) have been progressively recognized as potent bioactive compounds that play crucial roles in the modulation of several key biological processes, such as proliferation, differentiation, and apoptosis. Furthermore, SLs involvement in cardiac physiology and pathophysiology attracted much attention, since these molecules could be crucial in the development of CVDs. Among SLs, ceramide and sphingosine-1-phosphate (S1P) represent the most studied bioactive lipid mediators, which are characterized by opposing activities in the regulation of the fate of cardiac cells. In particular, maintaining the balance of the so-called ceramide/S1P rheostat emerged as an important novel therapeutical target to counteract CVDs. Thus, this review aims at critically summarizing the current knowledge about the antithetic roles of ceramide and S1P in cardiomyocytes dysfunctions, highlighting how the modulation of their metabolism through specific molecules, such as myriocin and FTY720, could represent a novel and interesting therapeutic approach to improve the management of CVDs.

Topics: Aged; Animals; Ceramides; Cerebrovascular Disorders; Coronary Disease; Humans; Lysophospholipids; Mice; Peripheral Arterial Disease; Pulmonary Embolism; Rheumatic Heart Disease; Sphingolipids; Sphingosine; Venous Thrombosis

Sphingolipids have emerged as key signaling molecules involved in the regulation of a variety of cellular functions including cell growth and differentiation, proliferation and apoptotic cell death. Sphingolipids in blood constitute part of the circulating lipoprotein particles (HDL, LDL and VLDL), carried by serum albumin and also present in blood cells and platelets. Recent lipidomic and proteomic studies of plasma lipoproteins have provided intriguing data concerning the protein and lipid composition of lipoproteins in the context of disease. Sphingolipids have been implicated in several diseases such as cancer, obesity, atherosclerosis and sphingolipidoses; however, efforts addressing blood sphingolipidomics are still limited. The development of methods to determine levels of circulating bioactive sphingolipids in humans and validation of these methods to be a routine clinical laboratory test could be a pioneering approach to diagnose disease in the population. This approach would probably evolve to be analogous in implication to determining "good" and "bad" cholesterol and triglyceride levels in lipoprotein classes.

Topics: Animals; Apoptosis; Atherosclerosis; Blood Cells; Coronary Disease; Diabetes Mellitus, Type 2; Homeostasis; Humans; Inflammation; Lipid Metabolism, Inborn Errors; Lipoproteins; Lysophospholipids; Sphingolipids; Sphingomyelin Phosphodiesterase; Sphingosine

Sphingosine-1-phosphate (S1P) is a bioactive sphingosine with antiatherosclerotic effects. The incidence of coronary heart disease (CHD) increases significantly among women after menopause. We explored the relationship between plasma S1P levels and the occurrence and severity of CHD in postmenopausal women.. Postmenopausal women admitted to our hospital for coronary angiography because of chest pain-like symptoms were included in our study. By 1:1 age matching (age difference ≤5 y), 166 women in the CHD group and control group were enrolled. The plasma S1P concentration was determined, and the Gensini score was calculated to decide the severity of CHD.. Plasma S1P levels were significantly lower in the CHD group of postmenopausal women ( P < 0.001). S1P (odds ratio, 0.952; 95% CI, 0.934-0.970) was an independent predictor of the occurrence of CHD in postmenopausal women. The area under the curve for S1P to predict the occurrence of CHD was 0.653 (95% CI, 0.595-0.712), and the cutoff value was 96.89 ng/mL. The plasma S1P level was the lowest in the high-tertile group of the Gensini score ( P < 0.001), and the plasma S1P (odds ratio, 0.948; 95% CI, 0.926-0.970) was an independent predictor of a high Gensini score in postmenopausal women with CHD.. Plasma S1P is an independent risk factor of the occurrence and severity of CHD in postmenopausal women. The occurrence and aggravation of CHD in postmenopausal women may be related to levels of S1P.

Topics: Coronary Disease; Female; Humans; Lysophospholipids; Postmenopause; Sphingosine

Coronary heart disease (CHD) risk inversely associates with levels of high-density lipoprotein cholesterol (HDL-C). The protective effect of HDL is thought to depend on its functionality, such as its ability to induce cholesterol efflux.. We compared plasma cholesterol efflux capacity between male familial hypercholesterolaemia (FH) patients with and without CHD relative to their non-FH brothers, and examined HDL constituents including sphingosine-1-phosphate (S1P) and its carrier apolipoprotein M (apoM).. Seven FH patients were asymptomatic and six had experienced a cardiac event at a mean age of 39 years. Compared to their non-FH brothers, cholesterol efflux from macrophages to plasma from the FH patients without CHD was 16 ± 22% (mean ± SD) higher and to plasma from the FH patients with CHD was 7 ± 8% lower (P = 0·03, CHD vs. non-CHD). Compared to their non-FH brothers, FH patients without CHD displayed significantly higher levels of HDL-cholesterol, HDL-S1P and apoM, while FH patients with CHD displayed lower levels than their non-FH brothers.. A higher plasma cholesterol efflux capacity and higher S1P and apoM content of HDL in asymptomatic FH patients may play a role in their apparent protection from premature CHD.

Topics: Adult; Aged; Apolipoprotein A-I; Apolipoprotein A-II; Apolipoproteins; Apolipoproteins M; Case-Control Studies; Cholesterol; Cholesterol, HDL; Coronary Disease; Heterozygote; Humans; Hyperlipoproteinemia Type II; Lipocalins; Lysophospholipids; Macrophages; Male; Middle Aged; Plasma; Protective Factors; Siblings; Sphingosine; Triglycerides; Young Adult

Impairment of coronary flow reserve (CFR) has been generally demonstrated in diabetic patients and animals with microvascular complications but without obvious obstructive coronary atherosclerosis. There have been few studies investigating CFR in cases of relatively well-controlled therapy. The purpose of this study is to evaluate the effect of treatment with a Sphingosine-1-phosphate (S1P) receptor potent agonist, FTY720, on early diabetic rats in terms of CFR. METHODS AND RESULTS: Male Sprague-Dawley (SD) rats were divided into 3 groups: (1) streptozotocin-uninjected rats (control rats); (2) streptozotocin-injected hyperglycemic rats (diabetic group); and (3) FTY720-fed and streptozotocin-injected hyperglycemic rats. FTY720 (1.25 mg/kg per day orally) was administrated for 9 weeks in SD rats (from 6 weeks old to 15 weeks old). CFR was evaluated by (13)NH3-positron emission tomography. No obvious pathological changes of macrovascular atherosclerosis were observed in each group. Diabetic rats had impaired CFR compared with the control group (1.39±0.26 vs. 1.94±0.24, P<0.05). Treatment with FTY720 for 9 weeks attenuated the heart histological changes and improved CFR in 32% of diabetic rats (1.84±0.36 vs. 1.39±0.26, P<0.05).. In summary, long-term therapy with the Sphingosine-1-phosphate receptor agonist, FTY720, improved CFR by attenuating the heart histological changes, and it might have a beneficial effect on coronary microvascular function in diabetic rats.

Topics: Ammonia; Animals; Blood Glucose; Capillaries; Cell Adhesion Molecules; Collagen; Coronary Circulation; Coronary Disease; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Drug Evaluation, Preclinical; Fingolimod Hydrochloride; Gene Expression Regulation; Interleukin-6; Lysophospholipids; Male; Microcirculation; Myocardium; Nitrogen Radioisotopes; Positron-Emission Tomography; Propylene Glycols; Rats; Rats, Sprague-Dawley; Receptors, Lysosphingolipid; Sphingosine; Transforming Growth Factor beta

High-density lipoprotein (HDL) has been shown to confer cardiovascular protection in clinical and epidemiologic studies. Emerging evidence suggests that many of the cardioprotective functions of HDL may be due to the phospholipid sphingosine-1-phosphate (S1P).. HDL-S1P binds to S1P receptors in the heart, activating PI3K/Akt signaling and myocyte survival. PI3K/Akt is a classic signaling modulator of autophagy. Excessive autophagy due to cell death and cardiomyocyte loss may contribute to impaired heart function during pressure overload-induced heart failure. Therefore, we hypothesize that HDL-S1P may suppress excessive autophagy of cardiomyocytes through activation of PI3K/Akt signaling. Further, reconstituted HDL (including S1P) may protect heart function during pressure overload-induced heart failure.. We will design the following experiments to test this hypothesis. (1) We will treat cells and mice with PI-3 kinase inhibitors to examine if HDL-S1P downregulates expression of Autophagy-related genes (ATGs) and proteins via activation of PI3K/Akt signaling. (2) We will use siRNA against S1P receptors or inhibitors of S1P receptors to determine which types of S1P receptors participate in this mechanism. (3) We will also examine if reconstituted HDL (including S1P) improves heart function during pressure overload-induced heart failure by suppressing excessive autophagy of cardiomyocytes through activation of PI3K/Akt signaling.. Understanding the autophagy signaling pathway modulated by HDL-S1P will make a major contribution to the field by identifying a novel mechanism for cardiovascular protection of high-density lipoprotein. Further, using reconstituted HDL to improve heart function would provide a novel therapeutic approach for pressure overload-induced heart failure.

Topics: Animals; Autophagy; Cardiotonic Agents; Coronary Disease; Heart Failure; Humans; Lipoproteins, HDL; Lysophospholipids; Myocytes, Cardiac; Sphingosine