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Gestational hypertension (GHTN) is associated with an increased cardiovascular risk for mothers and their offspring later in life. High-density lipoproteins (HDL) are anti-atherogenic by promoting efflux of cholesterol from macrophages and suppression of endothelial cell activation. Functional impairment of HDL in GHTN-complicated pregnancies may affect long-term health of both mothers and offspring. We studied functional parameters of maternal and neonatal HDL in 192 obese women (pre-pregnancy BMI ≥ 29), who were at high risk for GHTN. Maternal blood samples were collected longitudinally at <20 weeks, at 24–28 and 35–37 weeks of gestation. Venous cord blood was collected immediately after birth. Maternal and cord blood were used to determine functional parameters of HDL, such as HDL cholesterol efflux capacity, activity of the vaso-protective HDL-associated enzyme paraoxonase-1, and levels of the HDL-associated anti-inflammatory apolipoprotein (apo)M. In addition, we determined serum anti-oxidative capacity. Thirteen percent of the women were diagnosed with GHTN. While we found no changes in measures of HDL function in mothers with GHTN, we observed impaired HDL cholesterol efflux capacity and paraoxonase-1 activity in cord blood, while serum antioxidant capacity was increased. Of particular interest, increased maternal paraoxonase-1 activity and apoM levels in early pregnancy were associated with the risk of developing GHTN. GHTN significantly impairs HDL cholesterol efflux capacity as well as HDL PON1 activity in cord blood and could affect vascular health in offspring. Maternal paraoxonase-1 activity and apoM levels in early pregnancy associate with the risk of developing GHTN. [ABSTRACT FROM AUTHOR]

Apolipoprotein M (apoM) is a member of the lipocalin superfamily and is predominantly associated with high-density lipoprotein (HDL). It was found that apoM is the chaperon to the bioactive sphingolipid, sphingosine-1-phosphate (S1P). Several studies have since contributed to expand the knowledge on apoM, S1P, and the apoM/S1P-complex in cardiovascular diseases. For instance, the HDL-bound apoM/S1P complex serves as a bridge between HDL and endothelial cells, maintaining a healthy endothelial barrier. Evidence indicates, however, that the apoM/S1P complex may has both protective and harmful effects on the cardiovascular system, which suggests the need for more research to understand the interplay between these molecules. This review aims to shed light on the most recent findings on apoM/S1P-signaling and its impact on endothelial dysfunction, inflammation, and cardiovascular diseases. Finally, it will be discussed whether drugs that target apoM and/or S1P-signaling may be beneficial to patients with cardiovascular and inflammatory diseases. [Display omitted] • An imbalanced apoM/S1P-axis can interfere with triglyceride turnover and endothelial functions. • S1P-analogues may introduce a risk of disrupting the natural apoM/S1P axis and thereby the endothelial barrier homeostasis. • ApoM and S1P levels may predict the outcome of sepsis severity and SARS-CoV2. • ApoM and S1P may serve as a target in restoring endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Apolipoprotein M (apoM) is a member of the lipocalin superfamily and an important carrier of the small bioactive lipid sphingosine-1-phosphate (S1P). The apoM/S1P complex is attached to all lipoproteins, but exhibits a significant preference for high-density lipoproteins. Although apoM, S1P, and the apoM/S1P complex have been discovered more than a decade earlier, the overall function of the apoM/S1P complex remains controversial. Evidence suggests that the complex plays a role in inflammation and cholesterol metabolism and is important for maintaining a healthy endothelial barrier, regulating the turnover of triglycerides from lipoproteins, and reducing cholesterol accumulation in vessel walls. Recent studies have also addressed the role of apoM and S1P in the development of diabetes and obesity. However, limited evidence is available, and the data published so far deviates. This review discusses the specific elements indicative of the protective or harmful effects of apoM, S1P, and the apoM/S1P complex on type 2 diabetes development. Since drugs targeting the S1P system and its receptors are available and could be potentially used for treating diabetes, this research topic is a pertinent one. [ABSTRACT FROM AUTHOR]

Hepatocytes, renal proximal tubule cells as well as the highly specialized endotheliumof the blood brain barrier (BBB) express and secrete apolipoprotein M (apoM). ApoM is a typical lipocalin containing a hydrophobic binding pocket predominantly carrying Sphingosine-1-Phosphate (S1P). The small signaling molecule S1P is associated with several physiological as well as pathological pathways whereas the role of apoM is less explored. Hepatic apoM acts as a chaperone to transport S1P through the circulation and kidney derived apoM seems to play a role in S1P recovery to prevent urinal loss. Finally, polarized endothelial cells constituting the lining of the BBB express apoM and secrete the protein to the brain as well as to the blood compartment. The review will provide novel insights on apoM and S1P, and its role in hepatic fibrosis, neuroinflammation and BBB integrity. [ABSTRACT FROM AUTHOR]

Background 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. Materials and methods 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). Results 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. Conclusions 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. [ABSTRACT FROM AUTHOR]

Objective: The HDL associated apolipoprotein M (apoM) protects against experimental atherosclerosis but the mechanism is unknown. ApoM increases preβ-HDL formation. We explored whether plasma apoM affects mobilization of cholesterol from peripheral cells in mice. Methods and results: ApoM-enriched HDL from apoM-transgenic mice increased the in vitro efflux of 3H-cholesterol from macrophages by 24±3% (p<0.05) as compared with HDL from wild type (WT) mice, thus confirming previous findings. However, apoM-free HDL was not poorer than that of WT HDL to mobilize 3H-cholesterol. 3H-cholesterol-labeled foam cells were implanted in the peritoneal cavity of apoM−/−, WT and apoM-transgenic mice to assess the mobilization of cholesterol from foam cells in vivo and subsequent excretion into feces. The results showed a statistically non-significant trend towards increased mobilization of cellular cholesterol to plasma with increasing plasma apoM. However, the apoM-genotype did not affect the excretion of 3H-cholesterol in feces. Nevertheless, when apoM−/−, apoM-transgenic and WT mice received a constant intravenous infusion of 13C2-cholesterol/intralipid for 5h, the rate of enrichment of blood free cholesterol with free 13C2-cholesterol was significantly lower (consistent with an increase in flux of unlabeled free cholesterol into the plasma) in the apoM-transgenic (3.0±0.9‰/h) as compared to WT (5.7±0.9‰/h, p<0.05) and apoM−/− (6.5±0.6‰/h, p<0.01) mice. Conclusion: The present data indicate that the plasma apoM levels modulate the ability of plasma to mobilize cellular cholesterol, whereas apoM has no major effect on the excretion of cholesterol into feces. [ABSTRACT FROM AUTHOR]

Apolipoprotein M (apoM) is a plasma apolipoprotein that mainly associates with high-density lipoproteins. Hence, most studies on apoM so far have investigated its effect on and association with lipid metabolism and atherosclerosis. The insight into apoM biology recently took a major turn. ApoM was identified as a carrier of the bioactive lipid sphingosine-1-phosphate (S1P). S1P activates five different G-protein-coupled receptors, known as the S1P-receptors 1-5 and, hence, affects a wide range of biological processes, such as lymphocyte trafficking, angiogenesis, wound repair and even virus suppression and cancer. The ability of apoM to bind S1P is due to a lipophilic binding pocket within the lipocalin structure of the apoM molecule. Mice overexpressing apoM have increased plasma S1P concentrations, whereas apoM-deficient mice have decreased S1P levels. ApoM-S1P is able to activate the S1P-receptor-1, affecting the function of endothelial cells, and apoM-deficient mice display impaired endothelial permeability in the lung. This review will focus on the putative biological roles of the new apoM--S1P axis in relation to lipoprotein metabolism, lipid disorders and atherosclerosis. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Oxidation of LDL plays a key role in the development of atherosclerosis. HDL may, in part, protect against atherosclerosis by inhibiting LDL oxidation. Overexpression of HDL-associated apolipoprotein M (apoM) protects mice against atherosclerosis through a not yet clarified mechanism. Being a lipocalin, apoM contains a binding pocket for small lipophilic molecules. Here, we report that apoM likely serves as an antioxidant in HDL by binding oxidized phospholipids, thus enhancing the antioxidant potential of HDL. Methods and results: HDL was isolated from wild type mice, apoM-deficient mice, and two lines of apoM-Tg mice with ∼2-fold and ∼10-fold increased plasma apoM, respectively. Increasing amounts of HDL-associated apoM were associated with an increase in the resistance of HDL to oxidation with Cu2+ or 2,2′-azobis 2-methyl-propanimidamide, dihydrochloride (AAPH) and to an increased ability of HDL to protect human LDL against oxidation. Oxidized phospholipids, but not native phospholipids, quenched the intrinsic fluorescence of recombinant human apoM and the quenching could be competed with myristic acid suggesting selective binding of oxidized phospholipid in the lipocalin-binding pocket of apoM. Conclusions: The results suggest that apoM can bind oxidized phospholipids and that it increases the antioxidant effect of HDL. This new mechanism may explain at least part of the antiatherogenic potential of apoM. [Copyright &y& Elsevier]

Aim: Diabetes may lead to severe complications e.g. cardiac autonomic neuropathy (CAN) characterized by an increased risk of cardiovascular mortality. CAN is diagnosed by a decreased heart rate viability (HRV). Sphingosine-1-Phosphate (S1P) carried by the HDL-associated apolipoprotein M (apoM) is linked to a reduction in the heart rate, and treatment with an S1P-agonist increases HRV. The present study aimed to investigate if plasma apoM was associated with an increased risk of CAN.Methods: The study includes 278 individuals with Type 1 Diabetes recruited from Steno Diabetes Center in Copenhagen from 2010 to 2012.Results: A change of 0.1 µM plasma apoM was associated with the diagnosis of CAN (Odds ratio: 1.11 (1.02; 1.21), p = 0.013). ApoM plasma levels were also positively associated with CAN when adjusted for age and gender (Odds ratio: 1.11 (1.02; 1.21), p = 0.013) as well as lipids, beta-blockers, blood pressure, and alcohol (Odds ratio: 1.14 (1.04; 1.26), p = 0.005) and Hbga1c and time with diabetes (Odds ratio: 1.13 (1.02; 1.25), p = 0.01). Plasma apoM was also associated with a significantly lower SDNN as well as high frequency power in all adjusted models.Conclusion: Increased plasma apoM was associated with an increased risk of CAN as well as a significant reduction in HRV indices. This could represent changes in parasympathetic activity, but, further studies are needed to also explore additional molecular alterations behind such observations. [ABSTRACT FROM AUTHOR]