Acute myocardial infarction preferentially alters low-abundant, long-chain unsaturated phospholipid and sphingolipid species in plasma high-density lipoprotein subpopulations

Ponnaiah, Maharajah; Zakiev, Emile; Lhomme, Marie; Rached, Fabiana; Camont, Laurent; Serrano, Carlos V.; Santos, Raul D.; Chapman, M. John; Orekhov, Alexander; Kontush, Anatol

doi:10.1016/j.athplu.2023.12.001

Cited by 2 publications

References 39 publications

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Inhibition of Endothelial Lipase by MEDI5884 Normalizes Phosphatidylinositol Levels in Coronary Artery Disease Patients

Rosenbaum,

Huang,

et al. 2024

Preprint

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BackgroundEndothelial lipase (EL) promotes high-density lipoproteins (HDL) phospholipid degradation, increases catabolism of HDL and is an attractive target for the potential treatment for cardiovascular disease. Inhibition of EL using a monoclonal neutralizing antibody, MEDI5884, demonstrated increased quantity and function of HDL. Determinants of anti-atherosclerotic function of HDL comprise the interplay of various components of HDL structure-activity relationship: size, shape and composition (lipid and protein). Previous studies have shown that single doses of MEDI5884 administered to healthy nonhuman primates (NHPs) and healthy subjects resulted in a dose- dependent increase in plasma phospholipids (PL) and that plasma PI levels in placebo treated healthy subjects are significantly increased relative to CAD subjects participating in clinical trialsNCT03001297andNCT03351738, respectively.MethodsHerein, we characterized using LC-MS/MS the plasma lipidome of NHPs, heathy subjects and subjects with coronary artery disease (CAD) following MEDI5884 administration.ResultsMEDI5884 treated NHPs resulted in a prominent increase in phosphatidylinositols (PI) and cholesteryl esters (CE). Treatment with MEDI5884 restores near-normal levels of PI in CAD patients. PI increases in both healthy subjects and CAD patients were dose-dependent, correlated with exposure and saturated at approximately 200 mg MEDI5884 subcutaneous (SC) dose in CAD patients. Comparison of pharmacodynamic (PD) effects of repeat SC 200 mg doses of MEDI5884 in CAD patients revealed greater and more rapid increases in PI levels compared to HDL-C and HDL phospholipid (HDL-PL). The increase in PI species was inversely correlated with decreases in free EL mass levels.ConclusionsPI has previously been shown to possess anti-atherosclerotic properties and led to increases in HDL cholesterol (HDL-C) and reverse cholesterol transport (RCT). The mechanism by which CE levels increase as the result of MEDI5884 administration can be attributed to the observed increase in both substrates of the lecithin-cholesterol acyltransferase (LCAT) reaction: phosphatidylcholine/phosphatidylethanolamine (PC/PE) and cholesterol as the consequence of EL inhibition. Further characterization of the underlying biological mechanisms responsible for the decrease of the PI biomarker in CAD patient population relative to healthy subjects as well as in conjunction with pharmacological intervention by MEDI5884 may reveal more information on this clinically-relevant biomarker and potential role in CAD.

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Inhibition of Endothelial Lipase by MEDI5884 Normalizes Phosphatidylinositol Levels in Coronary Artery Disease Patients

Rosenbaum,

Huang,

et al. 2024

Preprint

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Vitamin D and Ceramide Metabolomic Profile in Acute Myocardial Infarction

Gaggini,

Marchi,

Pylypiv

et al. 2024

Metabolites

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Sphingolipids (SLs) influence several cellular pathways, while vitamin D exerts many extraskeletal effects in addition to its traditional biological functions, including the modulation of calcium homeostasis and bone health. Moreover, Vitamin D and SLs affect the regulation of each others’ metabolism; hence, this study aims to evaluate the relationship between the levels of 25(OH)D and ceramides in acute myocardial infarction (AMI). In particular, the blood abundance of eight ceramides and 25(OH)D was evaluated in 134 AMI patients (aged 68.4 ± 12.0 years, 72% males). A significant inverse correlation between 25(OH)D and both Cer(d18:1/16:0) and Cer(d18:1/18:0) was found; indeed, patients with severe hypovitaminosis D (<10 ng/mL) showed the highest levels of the two investigated ceramides. Moreover, diabetic/dyslipidemic patients with suboptimal levels of 25(OH)D (<30 ng/mL) had higher levels of both the ceramides when compared with the rest of the population. On the other hand, 25(OH)D remained an independent determinant for Cer(d18:1/16:0) (STD Coeff −0.18, t-Value −2, p ≤ 0.05) and Cer(d18:1/18:0) (−0.2, −2.2, p < 0.05). In light of these findings, the crosstalk between sphingolipids and vitamin D may unravel additional mechanisms by which these molecules can influence CV risk in AMI.

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Acute myocardial infarction preferentially alters low-abundant, long-chain unsaturated phospholipid and sphingolipid species in plasma high-density lipoprotein subpopulations

Cited by 2 publications

References 39 publications

Inhibition of Endothelial Lipase by MEDI5884 Normalizes Phosphatidylinositol Levels in Coronary Artery Disease Patients

Inhibition of Endothelial Lipase by MEDI5884 Normalizes Phosphatidylinositol Levels in Coronary Artery Disease Patients

Vitamin D and Ceramide Metabolomic Profile in Acute Myocardial Infarction

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