sphingosine-1-phosphate and Diabetic-Cardiomyopathies

In the setting of obesity and type 2 diabetes mellitus, the ectopic disposition of lipids may be a cause of heart failure. Clinical studies have clearly shown a correlation between the accumulation of triglycerides and heart dysfunction. In this process, it is likely that there are also changes in the contents of sphingolipids. Sphingolipids are important structural and signaling molecules. One specific sphingolipid, ceramide, may cause cardiac dysfunction, whereas another, sphingosine 1-phosphate, is cardioprotective. In this review, the authors focus on the role of sphingolipids in the development and prevention of cardiac failure.

Topics: Apoptosis; Ceramides; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Heart Failure; Humans; Lipid Metabolism; Lysophospholipids; Myocytes, Cardiac; Sphingolipids; Sphingosine

The dyslipidemia of type 2 diabetes mellitus has multiple etiologies and impairs lipoprotein functionality, thereby increasing risk for cardiovascular disease. High-density lipoproteins (HDLs) have several beneficial effects, notably protecting the heart from myocardial ischemia. We hypothesized that glycation of HDL could compromise this cardioprotective effect.. We used in vitro (cardiomyocytes) and ex vivo (whole heart) models subjected to oxidative stress together with HDL isolated from diabetic patients and nondiabetic HDL glycated in vitro (methylglyoxal). Diabetic and in vitro glycated HDL were less effective (P<0.05) than control HDL in protecting from oxidative stress. Protection was significantly, inversely correlated with the degree of in vitro glycation (P<0.001) and the levels of hemoglobin A1c in diabetic patients (P<0.007). The ability to activate protective, intracellular survival pathways involving Akt, Stat3, and Erk1/2 was significantly reduced (P<0.05) using glycated HDL. Glycation reduced the sphingosine-1-phosphate (S1P) content of HDL, whereas the S1P concentrations of diabetic HDL were inversely correlated with hemoglobin A1c (P<0.005). The S1P contents of in vitro glycated and diabetic HDL were significantly, positively correlated (both <0.01) with cardiomyocyte survival during oxidative stress. Adding S1P to diabetic HDL increased its S1P content and restored its cardioprotective function.. Our data demonstrate that glycation can reduce the S1P content of HDL, leading to increased cardiomyocyte cell death because of less effective activation of intracellular survival pathways. It has important implications for the functionality of HDL in diabetes mellitus because HDL-S1P has several beneficial effects on the vasculature.

Topics: Animals; Animals, Newborn; Case-Control Studies; Cell Survival; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dyslipidemias; Genotype; Glycated Hemoglobin; Glycosylation; Humans; Isolated Heart Preparation; Lipoproteins, HDL; Lysophospholipids; Male; Mice, Inbred C57BL; Mice, Knockout; Myocardial Reperfusion Injury; Myocytes, Cardiac; Oxidative Stress; Phenotype; Rats, Wistar; RNA Interference; Scavenger Receptors, Class B; Sphingosine; Time Factors; Transfection