Acid Sphingomyelinase Down‐regulation Alleviates Vascular Endothelial Insulin Resistance in Diabetic Rats

Li, Xin; Jin, Shijie; Su, Jie; Li, Xiao-Xue; Xu, Ming

doi:10.1111/bcpt.13073

Cited by 14 publications

(12 citation statements)

References 42 publications

(51 reference statements)

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“…ASM also plays a major role in the development of many other disorders such as cardiovascular and metabolic diseases. Its downregulation was reported to alleviate vascular endothelial insulin resistance in diabetic rats [152] and improve vascular dysfunction in diabetic mice [153]. Amitriptyline inhibits nonalcoholic steatohepatitis and atherosclerosis as induced by high-fat diet and lipopolysaccharide in mice [154].…”

Section: Assays For Studies Of Asm Inhibitorsmentioning

confidence: 99%

Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

Breiden¹,

Sandhoff

2021

IJMS

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Here, we present the main features of human acid sphingomyelinase (ASM), its biosynthesis, processing and intracellular trafficking, its structure, its broad substrate specificity, and the proposed mode of action at the surface of the phospholipid substrate carrying intraendolysosomal luminal vesicles. In addition, we discuss the complex regulation of its phospholipid cleaving activity by membrane lipids and lipid-binding proteins. The majority of the literature implies that ASM hydrolyses solely sphingomyelin to generate ceramide and ignores its ability to degrade further substrates. Indeed, more than twenty different phospholipids are cleaved by ASM in vitro, including some minor but functionally important phospholipids such as the growth factor ceramide-1-phosphate and the unique lysosomal lysolipid bis(monoacylglycero)phosphate. The inherited ASM deficiency, Niemann-Pick disease type A and B, impairs mainly, but not only, cellular sphingomyelin catabolism, causing a progressive sphingomyelin accumulation, which furthermore triggers a secondary accumulation of lipids (cholesterol, glucosylceramide, GM2) by inhibiting their turnover in late endosomes and lysosomes. However, ASM appears to be involved in a variety of major cellular functions with a regulatory significance for an increasing number of metabolic disorders. The biochemical characteristics of ASM, their potential effect on cellular lipid turnover, as well as a potential impact on physiological processes will be discussed.

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Section: Assays For Studies Of Asm Inhibitorsmentioning

confidence: 99%

Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

Breiden¹,

Sandhoff

2021

IJMS

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“…ASM catalyzes the hydrolysis of sphingomyelin to produce ceramide. Here, according to the methods described by Li et al [ 11 ], Palau et al [ 13 ] and Maroni et al [ 20 ], RAECs were incubated with an anti-ceramide antibody followed by goat anti-mouse IgG-FITC. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It has been established that Akt deficiency directly leads to decreased eNOS activity and NO production [ 51 ]. Our previous study also demonstrated that the phosphorylation of Akt is regulated by the ASM/ceramide pathway [ 11 ]. Moreover, a defect in the regulation of hypothalamic Akt signaling by leptin may be one of the mechanisms of central leptin resistance [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

“…Immunofluorescence of ceramide was measured according to the methods described by Li et al [ 11 ] and Palau et al [ 13 ]. RAECs were plated in a six-well plate.…”

Section: Methodsmentioning

confidence: 99%

“…Our previous study found that ASM contributes to the formation of membrane raft/redox signalosomes and mediates redox signaling in coronary arterial endothelial cells [ 10 ]. Moreover, the inhibition of ASM can alleviate insulin resistance in endothelial cells of diabetic rats [ 11 ]. However, it has never been reported whether ASM can influence leptin resistance in vascular endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

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Acid sphingomyelinase downregulation alleviates vascular endothelial leptin resistance in rats

Cai

2019

Acta Pharmacol Sin

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Leptin resistance in endothelial cells leads to vascular endothelial dysfunction, which is the beginning and crucial link of atherosclerosis. However, the mechanism of leptin resistance remains obscure. Acid sphingomyelinase (ASM) catalyzes the hydrolysis of sphingomyelin to produce ceramide, which plays an important role in the progression of metabolic and cardiovascular diseases. In this study, we investigated whether ASM could regulate leptin resistance in vascular endothelial cells. We induced endothelial leptin resistance in rat aortic endothelial cells through treatment with palmitic acid (0.3 mM) or knockdown of leptin receptor (Ob-Rb), which resulted in the increase of suppressor of cytokine signaling 3 expression, the decrease of Ob-Rb expression, and signal transducer and activator of transcription 3 (STAT3) phosphorylation at Tyr705. We found that these indicators of leptin resistance were reversed by knockdown of ASM or by the selective ASM inhibitors amitriptyline (AMI) and imipramine (IMI). Supplementation of ceramide inhibited Ob-Rb expression and STAT3 phosphorylation by inhibiting extracellular signal-regulated kinase 1/2 activation. Furthermore, we found that knockdown of ASM enhanced endothelial nitric oxide (NO) synthase activity and NO production, as well as the Akt phosphorylation at ser473, which was regulated by STAT3. High-fat diet (HFD) feeding-induced leptin resistance in rats in vivo; administration of AMI and IMI (10 mg· kg −1 per day, intraperitoneally, for 2 weeks) increased the release of endothelial NO to relieve the vasodilatory response and improved the endothelial leptin resistance in the aorta of HFD-fed rats. These results suggest that ASM downregulation reverses endothelial leptin resistance, and consequently improves vascular endothelial dysfunction. This study highlighted ASM as a potential therapeutic target for endothelial leptin resistance.

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The Acid Sphingomyelinase Inhibitor Amitriptyline Ameliorates TNF-α-Induced Endothelial Dysfunction

Chen

Pang

et al. 2022

Cardiovasc Drugs Ther

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Purpose Inflammation associated endothelial cell (EC) dysfunction is key to atherosclerotic disease. Recent studies have demonstrated a protective role of amitriptyline in cardiomyocytes induced by hypoxia/reoxygenation. However, the mechanism by which amitriptyline regulates the inflammatory reaction in ECs remains unknown. Thus, the aim of this study was to investigate whether amitriptyline protects against inflammation in TNF-α-treated ECs. Methods HUVECs were incubated with amitriptyline (2.5 μM) or TNF-α (20 ng/ml) for 24 h. EdU, tube formation, transwell, DHE fluorescence staining, and monocyte adhesion assays were performed to investigate endothelial function. Thoracic aortas were isolated from mice, and vascular tone was measured with a wire myograph system. The levels of ICAM-1, VCAM-1, MCP-1, phosphorylated MAPK and NF-κB were detected using western blotting. Results Amitriptyline increased the phosphorylation of nitric oxide synthase (eNOS) and the release of NO. Amitriptyline significantly inhibited TNF-α-induced increases in ASMase activity and the release of ceramide and downregulated TNF-α-induced expression of proinflammatory proteins, including ICAM-1, VCAM-1, and MCP-1 in ECs, as well as the secretion of sICAM-1 and sVCAM-1. TNF-α treatment obviously increased monocyte adhesion and ROS production and impaired HUVEC proliferation, migration and tube formation, while amitriptyline rescued proliferation, migration, and tube formation and decreased monocyte adhesion and ROS production. Additionally, we demonstrated that amitriptyline suppressed TNF-α-induced MAPK phosphorylation as well as the activity of NF-κB in HUVECs. The results showed that the relaxation response of aortic rings to acetylcholine in the WT-TNF-α group was much lower than that in the WT group, and the sensitivity of aortic rings to acetylcholine in the WT-TNF-α group and WT-AMI-TNF-α group was significantly higher than that in the WT-TNF-α group. Conclusion These results suggest that amitriptyline reduces endothelial inflammation, consequently improving vascular endothelial function. Thus, the identification of amitriptyline as a potential strategy to improve endothelial function is important for preventing vascular diseases.

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Acid Sphingomyelinase Down‐regulation Alleviates Vascular Endothelial Insulin Resistance in Diabetic Rats

Cited by 14 publications

References 42 publications

Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism

Acid sphingomyelinase downregulation alleviates vascular endothelial leptin resistance in rats

The Acid Sphingomyelinase Inhibitor Amitriptyline Ameliorates TNF-α-Induced Endothelial Dysfunction

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