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Panax Notoginseng Saponins Protect Cardiac Myocytes Against Endoplasmic Reticulum Stress and Associated Apoptosis Through Mediation of Intracellular Calcium Homeostasis.

ABSTRACT: Endoplasmic reticulum (ER) stress has been demonstrated to play important roles in the pathogenesis of various cardiovascular diseases. The ER stress pathway is therefore a promising therapeutic target in cardiovascular disease. Although Panax notoginseng saponins (PNS) are one of the patent medicines that are traditionally used to treat cardiovascular disorders, their effects on ER stress in cardiac myocytes remain unexploited so far. This study investigates the effects of PNS on ER stress and its associated cell apoptosis along with the related mechanism in cardiac myocytes. PNS compounds were identified via high-performance liquid chromatograph (HPLC) assay. PNS-pretreated H9c2 cells, HL-1 cells, and primary cultured neonatal rat cardiomyocytes were stimulated with thapsigargin (TG) to induce ER stress response and apoptosis. ER stress response was tested by immunofluorescence or immunoblot of the ER protein chaperones-calnexin, binding immunoglobulin protein (BiP) and the C/EBP homologous protein (CHOP). Cell viability was tested by methyl thiazolyl tetrazolium (MTT) assay. Cell apoptosis was detected by immunoblot of Cleaved caspase-3 and flow cytometry analysis of Annexin V/propidium iodide (PI) staining. Cytosolic, mitochondrial, and ER calcium dynamics were investigated by calcium imaging. Moreover, a ryanodine receptor type-2 (RyR2) overexpression stable cell line was generated to verify the mechanism of RyR2 involved in PNS in the inhibition of ER stress and cell apoptosis. We demonstrate here that PNS protected cardiac myocytes from ER stress response and associated cell death in a concentration-dependent manner. Importantly, PNS reduced the elevation of cytosolic calcium, mitochondria calcium, as well as ER calcium in response to either TG or histamine treatment. PNS protection in ER stress was regulated by RyR2 expression. In summary, PNS protection against TG-induced ER stress response and its associated cell apoptosis in cardiac myocytes is calcium dependent. Through the regulation of ER calcium release mediated by RyR2, a novel mechanism for PNS in the prevention of cardiovascular diseases is thereby identified.

SUBMITTER: Chen J

PROVIDER: S-EPMC6764115 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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<i>Panax Notoginseng Saponins</i> Protect Cardiac Myocytes Against Endoplasmic Reticulum Stress and Associated Apoptosis Through Mediation of Intracellular Calcium Homeostasis.

Chen Jun J Xue Rui R Li Li L Xiao Li Li LL Shangguan Jiahong J Zhang Wenjing W Bai Xueyang X Liu Gangqiong G Li Ling L

Frontiers in pharmacology 20190920

Endoplasmic reticulum (ER) stress has been demonstrated to play important roles in the pathogenesis of various cardiovascular diseases. The ER stress pathway is therefore a promising therapeutic target in cardiovascular disease. Although <i>Panax notoginseng</i> saponins (PNS) are one of the patent medicines that are traditionally used to treat cardiovascular disorders, their effects on ER stress in cardiac myocytes remain unexploited so far. This study investigates the effects of PNS on ER stre ...[more]

PMID: 31616293

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Project description:Statins cannot be used for some active liver diseases, which limits its application to some extent. The combined use of statins with other drugs may be one of the ways to solve this dilemma.This research aims to evaluate the effects of atorvastatin combined with Panax notoginseng saponins (PNS) on rats with atherosclerosis (AS) complicated with hepatic injury.Seventy-two male Wistar rats were randomly categorized into control group (without any intervention, Group A) and AS model groups, which were divided into hepatic injury (Groups B-E) and nonhepatic injury (Groups F-I) groups. Hepatic and nonhepatic injury groups were intragastrically treated with 5.5 mg/kg·d atorvastatin (Group B, F), 200 mg/kg·d PNS (Group C, G), 5.5 mg/kg·d atorvastatin + 200 mg/kg·d PNS (Group D, H), and normal saline (Group E, I). After 8 weeks, total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol, low density lipoprotein-cholesterol (LDL-C), and serum calcium were analyzed to evaluate the hypolipidemic effect. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and r-glutamyltransferase levels were measured to assess liver function. The thoracic aortas were used for hematoxylin-eosin staining.In both hepatic injury and nonhepatic injury groups, TC, TG and LDL-C levels significantly decreased in Groups B, D, F, and H. ALT and AST levels significantly increased in Group B, but significantly decreased in Groups C and D. The aortic intima thickness was significantly lower in Groups B, D, F, and H than that in the normal saline group.The combination of atorvastatin and PNS treatment showed a significant hypolipidemic effect and hepatic enzyme stability function.The single use of Panax notoginseng saponins (PNS) in the rat model for atherosclerosis significantly reduced Ca2+ content in serum, whereas the effect of lowing total cholesterol (TC), triglyceride (TG), and low density lipoprotein-cholesterol (LDL-C) is not apparent, especially as compared with atorvastatin treatmentPNS combined with atorvastatin treatment of the rat model for atherosclerosis displayed a noticeable, synergistic effect that allowed for better reduction of TC, TG, LDL-C and Ca2+ in the serum than that with the single use of PNS or atorvastatinIn the rat liver injury combined with atherosclerosis model, the single use of PNS significantly improved liver function, whereas atorvastatin alone only aggravated liver injury in the rat model. The effect of PNS combined with atorvastatin on liver function was significantly better than that of atorvastatin aloneThe combined use of PNS and atorvastatin showed good stability of liver function on the liver injury combined with atherosclerosis model. Abbreviations used: PNS: Panax notoginseng saponins; AS: Atherosclerosis; TC: Total cholesterol; TG: Triglyceride; HDL-C: High density lipoprotein-cholesterol; LDL-C: Low density lipoprotein-cholesterol; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; T-BIL: Total bilirubin; r-GT: R-glutamyltransferase; HE: Hematoxylin-eosin.

Dataset Information

Panax Notoginseng Saponins Protect Cardiac Myocytes Against Endoplasmic Reticulum Stress and Associated Apoptosis Through Mediation of Intracellular Calcium Homeostasis.

Publications

<i>Panax Notoginseng Saponins</i> Protect Cardiac Myocytes Against Endoplasmic Reticulum Stress and Associated Apoptosis Through Mediation of Intracellular Calcium Homeostasis.

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