Matrine attenuates high‐fat diet‐induced in vivo and ox‐LDL‐induced in vitro vascular injury by regulating the PKCα/eNOS and PI3K/Akt/eNOS pathways

Abstract

Lipid metabolism disorders lead to vascular endothelial injury. Matrine is an alkaloid that has been used to improve obesity and diabetes and for the treatment of hepatitis B. However, its effect on lipid metabolism disorders and vascular injury is unclear. Here, we investigated the effect of matrine on high‐fat diet fed mice and oxidized low‐density lipoprotein (ox‐LDL)‐induced human umbilical vein endothelial cells (HUVECs). Computational virtual docking analyses, phosphoinositide 3‐kinase (PI3K) and protein kinase C‐α (PKCα) inhibitors were used to localize matrine in vascular injuries. The results showed that matrine‐treated mice were more resistant to abnormal lipid metabolism and inflammation than vehicle‐treated mice and exhibited significantly alleviated ox‐LDL‐stimulated dysfunction of HUVECs, restored diminished nitric oxide release, decreased reactive oxygen species generation and increased expression phosphorylation of AKT‐Ser473 and endothelial nitric oxide synthase (eNOS)‐Ser1177. Matrine not only up‐regulates eNOS‐Ser1177 but also down‐regulates eNOS‐Thr495, a PKCα‐controlled negative regulator of eNOS. Using computational virtual docking analyses and biochemical assays, matrine was also shown to influence eNOS/NO via PKCα inhibition. Moreover, the protective effects of matrine were significantly abolished by the simultaneous application of PKCα and the PI3K inhibitor. Matrine may thus be potentially employed as a novel therapeutic strategy against high‐fat diet‐induced vascular injury.

Endothelial S1pr1 regulates pressure overload‐induced cardiac remodelling through AKT‐eNOS pathway

“…To test whether AKT activity could be enhanced by S1P/S1pr1 stimulation in endothelial cells, we performed Western blot analysis and our results showed that the active levels of AKT was significantly higher in S1PR1‐overexpressing HUVECs (human umbilical venous endothelial cells) after S1P challenge (Figure F), suggesting S1P activated AKT signalling pathway via S1pr1 in ECs. In endothelial cells, eNOS signalling pathway plays an essential role in the regulation of endothelial function and has been shown as one downstream target of AKT signalling pathway . We next investigated whether S1P/S1PR1 praxis influenced eNOS signalling pathway in ECs.…”

“…11,12 We next investigated whether S1P/S1PR1 praxis influenced eNOS signalling pathway in ECs. In endothelial cells, eNOS signalling pathway plays an essential role in the regulation of endothelial function and has been shown as one downstream target of AKT signalling pathway.…”

Matrine: A Promising Natural Product With Various Pharmacological Activities

“…The signaling axis formed by PI3K and AKT, as well as the vast range of downstream substrates is thus central to control of cell physiology in many different contexts and tissues (Noorolyai et al, 2019;Sugiyama et al, 2019). Matrine inhibits the PI3K/ AKT pathway in tumor cells, while the reverse occurs in normal cells (Niu et al, 2014;Xie et al, 2015;Liu S. Q. et al, 2017;Wu X. et al, 2017;Chen et al, 2019;Zhang et al, 2019). Moreover, for tumor cells, matrine induces oxidative stress leading to endogenous apoptosis in cells, while in ischemic disease models, matrine inhibits oxidative stress and thereby inhibits apoptosis of nerve cells and cardiac muscle cells.…”

“…software) and biochemical analysis showed that matrine affected eNOS/NO by inhibiting PKCa, and the protective effect of matrine could be eliminated by using PKCa and PI3K inhibitors (Zhang et al, 2019). Liu et al (2018) reported that matrine can reduce AGEs-mediated Notch signal activation in human coronary smooth muscle cells (HCSMC), downregulate the expression levels of nicd1, hes1, collagen I, collegen VIII, and collagen secretion in HCSMC, and block the precondition of atheromatous plaque formation.…”

Research Progress on Anti‐Inflammatory Effects and Mechanisms of Alkaloids from Chinese Medical Herbs

“…Matrine, extracted from the root of Sophora flavescens, has therapeutic effects on rheumatoid arthritis, psoriasis, ulcerative colitis, ankylosing spondylitis, asthma, acute lung injury, acute respiratory distress syndrome, and cerebral infarction [58].…”