Sacubitril/valsartan inhibits ox‑LDL‑induced MALAT1 expression, inflammation and apoptosis by suppressing the TLR4/NF‑κB signaling pathway in HUVECs

Abstract

The therapeutic effect of sacubitril/valsartan (S/V) on heart failure has been confirmed, while its role in atherosclerosis remains largely unexplored. The present study aimed to investigate the effects of S/V on the expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), inflammation and apoptosis in human umbilical vein endothelial cells (HUVECs) induced by oxidized low-density lipoprotein (ox-LDL) and to elucidate its possible mechanism. Cell Counting Kit-8 assay was used to detect cell viability. Reverse transcription-quantitative PCR was performed to detect the MALAT1 expression. ELISA was performed to detect the levels of IL-1β, IL-6 and TNF-α. Flow cytometry was conducted to detect the apoptotic rate of cells. A nitric oxide (NO) detection kit was used to determine the concentration of NO. Western blotting analysis was performed to determine the levels of intercellular cell adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, endothelin-1, caspase-3, Bax, Bcl-2, Toll-like receptor 4 (TLR4), p65 and p-p65. Compared with the ox-LDL group, S/V treatment significantly increased the cell viability, NO concentration and Bcl-2 expression, decreased the levels of IL-1β, IL-6 and TNF-α and reduced the expressions of MALAT1, ICAM-1, VCAM-1, cleaved-caspase-3, Bax, TLR4 and p-p65. Overall, the findings suggested that S/V could downregulate the expression of MALAT1, inhibit inflammation and apoptosis and improve endothelial function in ox-LDL-induced HUVECs via inactivating the TLR4/NF-κB signaling pathway. Therefore, S/V might be utilized as a promising therapeutic strategy for the prevention and treatment of atherosclerosis.

A novel circulating biomarker lnc‐MALAT1 for acute myocardial infarction: Its relationship with disease risk, features, cytokines, and major adverse cardiovascular events

“…According to previous studies, lipid profile, cTnI, infarct size, inflammation, and adhesion molecules are viewed as hallmarks of AMI 22 , 23 , 24 ; thus, we explored the association of lnc‐MALAT1 with them among AMI patients, which showed that lnc‐MALAT1 was positively linked with lipid dysregulation (reflected by LDL‐C), the marker of myocardial injury (reflected by cTnI), disease severity indicator (reflected by infarct size), systematic inflammation (reflected by CRP, TNF‐α, IL‐6, and IL‐17A), and adhesion cytokines (reflected by VCAM‐1 and ICAM‐1). The potential explanations might be that (1) lnc‐MALAT1 could accelerate lipid metabolism and lipid oxidation in AMI, which resulted in elevated LDL‐C 25 ; (2) lnc‐MALAT1 might promote cardiomyocyte injury through several mechanisms, such as regulating autophagy‐related 3, as well as phosphatase and tensin homolog deleted on chromosome 10, which led to increased cTnI and infarct size in AMI 26 , 27 ; (3) lnc‐MALAT1 might be able to accelerate inflammation by regulating several signaling pathways, including Wnt/β‐catenin and nuclear factor‐kappa B signaling; thereby, lnc‐MALAT1 was positively associated with inflammation in AMI patients 28 , 29 ; and (4) lnc‐MALAT1 could accelerate the production of adhesion molecules through several methods, such as microRNA‐590 and the signal transducer and activator of transcription 3 pathway 21 ; thus, a positive relation was found in lnc‐MALAT1 with adhesion cytokines among AMI patients. In addition, we also discovered that higher lnc‐MALAT1 was linked with a history of DM among AMI patients.…”

“…lnc-MALAT1 could accelerate lipid metabolism and lipid oxidation in AMI, which resulted in elevated LDL-C 25 ; (2) lnc-MALAT1 might promote cardiomyocyte injury through several mechanisms, such as regulating autophagy-related 3, as well as phosphatase and tensin homolog deleted on chromosome 10, which led to increased cTnI and infarct size in AMI26,27 ; (3) lnc-MALAT1 might be able to accelerate inflammation by regulating several signaling pathways, including Wnt/β-catenin and nuclear factor-kappa B signaling; thereby, lnc-MALAT1 was positively associated with inflammation in AMI patients28,29 ; and (4) lnc-MALAT1 could accelerate the production of adhesion molecules through several methods, such as microR-NA-590 and the signal transducer and activator of transcription 3 pathway21 ; thus, a positive relation was found in lnc-MALAT1 with adhesion cytokines among AMI patients.…”

Valsartan in Combination with Tripterygium Glycosides Protects against Chronic Nephritis via the Toll-Like Receptor 4 Pathway

“…As for the impacts of valsartan and tripterygium glycosides on TLR4 expression, a related study has reported that valsartan prevents glycerol-stimulated acute kidney injury via reducing the TLR4 and NF-kappaB expression [ 24 ]. Furthermore, in heart failure, it has been evidenced that valsartan can mitigate the inflammatory response by reducing TLR4 expression [ 25 ].…”

The history and mystery of sacubitril/valsartan: From clinical trial to the real world

“…Sacubitril/valsartan inhibits oxidized low-density lipoprotein-induced apoptosis in human umbilical vein endothelial cells and ameliorates endothelial injury by inhibiting the TLR4/NF-κB signaling pathway and downregulating metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression ( 24 ). Administration of sacubitril/valsartan to rats fed a high-protein diet with CRS downregulates mitofusin 2 (Mfn2) expression, inhibits mitochondrial division, protects the functional integrity of mitochondria, inhibits apoptosis, and improves cardiac function ( 25 ).…”