Sphingolipid therapy in myocardial ischemia–reperfusion injury

Abstract

Sphingolipids are known to play a significant physiological role in cell growth, cell differentiation, and critical signal transduction pathways. Recent studies have demonstrated a significant role of sphingolipids and their metabolites in the pathogenesis of myocardial ischemia-reperfusion injury. Our laboratory has investigated the cytoprotective effects of N,N,N-Trimethylsphingosine chloride (TMS), a stable N-methylated synthetic sphingolipid analogue on myocardial and hepatic ischemia reperfusion injury in clinically relevant in vivo murine models of ischemia-reperfusion injury. TMS administered intravenously at the onset of ischemia reduced myocardial infarct size in the wild-type and obese (ob/ob) mice. Following myocardial I/R, there was an improvement in cardiac function in the wild-type mice. Additionally, TMS also decreased serum liver enzymes following hepatic I/R in wild-type mice. The cytoprotective effects did not extend to the ob/ob mice following hepatic I/R or to the db/db mice following both myocardial and hepatic I/R. Our data suggests that although TMS is cytoprotective following I/R in normal animals, the cytoprotective actions of TMS are largely attenuated in obese and diabetic animals which may be due to altered signaling mechanisms in these animal models. Here we review the therapeutic role of TMS and other sphingolipids in the pathogenesis of myocardial ischemia reperfusion injury and their possible mechanisms of cardioprotection.

Metabolomics Study of Resina Draconis on Myocardial Ischemia Rats Using Ultraperformance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry Combined with Pattern Recognition Methods and Metabolic Pathway Analysis

“…Sphingolipids are highly bioactive compounds and are involved in diverse cell processes, including cell-cell interaction, cell proliferation, cell differentiation, and apoptosis [34]. Emerging evidence has shown that sphingolipid-mediated signal transduction pathways play a significant role in cardiovascular pathophysiology [35]. In our study, three phospholipids, including phytosphingosine, sphinganine, and hexadecasphinganine, had increased levels in MI group, showing the activated sphingolipid metabolism.…”

Large-scale Metabolomic Analysis Reveals Potential Biomarkers for Early Stage Coronary Atherosclerosis

“…Sphingolipids, which are a large class of lipids, play important roles as both membrane components and signaling molecules involved in diverse cell processes, including cell-cell interactions, cell proliferation, cell differentiation, and apoptosis 38 . Emerging evidence has shown that sphingolipid-mediated cellular signaling pathways play a critical role in cardiovascular pathophysiology 39 . It has been reported that sphingolipids have the capacity to reduce triglyceride and cholesterol levels 40 .…”

Thematic Review Series: Sphingolipids. Biodiversity of sphingoid bases (“sphingosines”) and related amino alcohols

“…Safingol is acylated by mammalian ceramide synthase(s) ( 114 ) and was recently found to undergo substantial N -methylation (to N -methyl, N , N -dimethyl, and N , N , N -trimethyl derivatives) ( 47 ), which is interesting because N , N -dimethylsphingosine is cytotoxic for many cancer cell lines ( 51 , 206 , 207 ) (and presumably, the same may be the case for N , N -dimethylsafingol, 85 ). The formation of N -methyl derivatives in vivo is also interesting because administration of N , N , N -trimethylsphingosine ( 86 ) intravenously at the onset of ischemia has been found to reduce myocardial infarct size and improvement in cardiac function ( 208 ).…”