Quaternary ammonium salt of U50,488H elicits protective effects against hypoxic pulmonary hypertension

Zhou, Yunyun; Tian, Xiujuan; Wang, Yuanbo; Fan, Rong; Wang, Yuemin; Feng, Na; Zhang, Shumiao; Guo, Hongwei; Gu, Xiaoming; Jia, Min; Yin, Wen; Hou, Zuoxu; Li, Juan; Pei, Jianming

doi:10.1016/j.ejphar.2018.05.025

Cited by 5 publications

(4 citation statements)

References 34 publications

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“…at 4°C, and the supernatant was collected and stored at −20°C. Endothelial nitric oxide synthase (eNOS) activity and nitric oxide level were measured using commercially available kits (Nanjing Jingcheng Bioengineering Institute, Nanjing, China) according to the manufacturer's instructions . Nitric oxide synthase (NOS) catalyzed l ‐arginine and molecular oxygen reaction to produce nitric oxide and then nitric oxide reacted with nucleophile to produce the coloured compound which was measured at 530 nm wavelength.…”

Section: Methodsmentioning

confidence: 99%

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

Jin

et al. 2018

Basic Clin Pharma Tox

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Insulin resistance in endothelial cells contributes to the development of cardiovascular disease in patients with type 2 diabetes. Acid sphingomyelinase (ASM) is a soluble glycoprotein which plays a vital role in the development and progression of various diseases such as cardiovascular and metabolic diseases. However, it remains unknown if ASM regulates insulin resistance in vascular endothelial cells in type 2 diabetes. ASM down-regulation with gene silencing and selective inhibitor amitriptyline was used in the rat aortic endothelial cells (RAECs) treated with palmitic acid (PA), a common saturated free fatty acid, which is thought to be the major cause of insulin resistance. It was shown that ASM down-regulation increased glucose uptake and glucose transporter-4 (Glut4) expression and reversed the phosphorylation of pIRS-1-ser307 and AKT-ser473 via ceramide, consequently resulting in the decrease of the production of endothelial nitric oxide synthase (eNOS) and nitric oxide in PA-induced RAECs. We further found that ASM down-regulation blocked the Nox2- and Nox4-dependent superoxide (O ) generation, which regulated glucose metabolism in RAECs during PA stimulation. In vivo, amitriptyline relieved the vasodilatory response to acetylcholine and restored the level of ceramide, Nox2 and Nox4 in the aorta endothelium of high-fat diet-fed rats following an injection of streptozotocin. Taken together, these results suggest that ASM down-regulation can improve endothelial insulin resistance which is attributed to inhibiting redox signalling in RAECs. Thus, these data support the idea that ASM is a promising clinical biomarker and potential therapeutic target for diabetic vascular complication.

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Section: Methodsmentioning

confidence: 99%

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

Jin

et al. 2018

Basic Clin Pharma Tox

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“…A large number of studies have demonstrated that PIM1 is overactivated in patients with PH, preclinical animal models, or cell models [25][26][27] , and inhibition of PIM1 expression by drug intervention could also effectively delay the progression of PH 26,28 . NOS3, also known as eNOS, is mainly expressed in endothelial cells and could play a protective role in PH vascular remodeling by regulating nitric oxide synthesis [29][30][31] . The above studies show that SRC and PIM1 may participate in the development of PH by promoting the proliferation of PASMCs.…”

Section: Discussionmentioning

confidence: 99%

Evaluating the Therapeutic Role of Selected Active Compounds in Plumula Nelumbinis on Pulmonary Hypertension via Network Pharmacology and Experimental Analysis

Xiao

Luo

et al. 2022

Preprint

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Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the most critical factors leading to vascular remodeling in pulmonary hypertension (PH). This study aimed to explore the effect and potential mechanism of Plumula Nelumbinis on PH by using network pharmacology and experimental analysis. The potential active components of Plumula Nelumbinis and their targets were obtained from TCMSP and PharmMapper databases. The PH-related targets were obtained from GeneCards, OMIM, DisGeNET, and TTD databases. Co-targets between Plumula Nelumbinis and PH were obtained by drawing Venn diagrams. The protein-protein interaction networks and compound-target-pathway networks were established using the STRING database and Cytoscape software. Moreover, the binding activities of core targets and essential active compounds were further validated by molecular docking. Finally, we further confirmed in vitro experiments that the main active components of Plumula Nelumbinis could inhibit the proliferation of PASMCs induced by hypoxia, as well as the increased expression of p-SRC and PIM1. Based on these observations, we conclude that multi-components (neferine, liensinine, and isoliensinine) in Plumula Nelumbinis can inhibit the hypoxia-induced proliferation of PASMCs by regulating the expression of p-SRC and PIM1, thereby delaying the development of PH.

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“…The enhanced intracellular Ca 2+ transient and L-type Ca 2+ currents elicited by isoprenaline in cardiomyocytes were significantly inhibited by U50,488H, both of which provide evidence that U50,488H reduces myocardial calcium influx and oxidative stress [ 31 ]. However, our previous study demonstrated that administration of U50,488H significantly decreased mean pulmonary arterial pressure and right ventricular hypertrophy, showing promise in attenuating vascular remodeling [ 38 ]. We also found that U50,488H interacted with the calcium-sensing receptor (CaSR) in the pulmonary artery and inhibited pulmonary hypertension and vascular remodeling through the CaSR/MAPK signaling pathway [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

κ-opioid receptor stimulation alleviates rat vascular smooth muscle cell calcification via PFKFB3-lactate signaling

Niu

Zhang

et al. 2021

Aging

Self Cite

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In the present study, the effects and mechanism of action of U50,488H (a selective κ-opioid receptor agonist) on calcification of rat vascular smooth muscle cells (VSMCs) induced by β-glycerophosphate (β-GP) were investigated. VSMCs were isolated and cultured in traditional FBS-based media. A calcification model was established in VSMCs under hyperphosphatemia and intracellular calcium contents. Alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and lactate were detected in cell culture supernatants before and after treatment. Alizarin red staining was used to detect the degree of calcification of VSMCs. Expression levels of key molecules of osteogenic markers, fructose-2,6-biphosphatase 3 (PFKFB3), and proline hydroxylase 2 (PHD2), were determined using western blotting. Further, vascular calcification was induced by vitamin D3 plus nicotine in rats and isolated thoracic aortas, calcium concentration was assessed in rat aortic rings in vitro . We demonstrated that U50,488H inhibited VSMC calcification in a concentration-dependent manner. Moreover, U50,488H significantly inhibited osteogenic differentiation and ALP activity in VSMCs pretreated with β-GP. Further studies confirmed that PFKFB3 expression, LDH level, and lactate content significantly increased during calcification of VSMCs; U50,488H reversed these changes. PHD2 expression showed the opposite trend compared to PFKFB3 expression. nor-BNI or 3-PO abolished U50,488H protective effects. Besides, U50,488H inhibited VSMC calcification in rat aortic rings ex vivo . Collectively, our experiments show that κ-opioid receptor activation inhibits VSMC calcification by reducing PFKFB3 expression and lactate content, providing a potential drug target and strategy for the clinical treatment of vascular calcification.

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Quaternary ammonium salt of U50,488H elicits protective effects against hypoxic pulmonary hypertension

Cited by 5 publications

References 34 publications

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

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

Evaluating the Therapeutic Role of Selected Active Compounds in Plumula Nelumbinis on Pulmonary Hypertension via Network Pharmacology and Experimental Analysis

κ-opioid receptor stimulation alleviates rat vascular smooth muscle cell calcification via PFKFB3-lactate signaling

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