LCZ696 ameliorates lipopolysaccharide-induced endothelial injury

Abstract

Lipopolysaccharide (LPS)-induced endothelial dysfunction plays an important role in the pathogenesis of cardiovascular diseases. LCZ696, the dual-acting angiotensin receptor blocker, and neprilysin inhibitor has been used for the treatment of heart failure with reduced ejection fraction. Recent work suggests that LCZ696 therapy might have an anti-inflammatory effect in cardiovascular tissue. In the current study, we show that LCZ696 attenuates LPS-induced oxidative stress by reducing the production of intracellular reactive oxygen species (ROS) and the measurements of malonyl dialdehyde (MDA) level in human umbilical vascular endothelial cells (HUVECs). LCZ696 inhibits LPS-induced expressions and secretions of the pro-inflammatory cytokines, interleukin-6 (IL-6), interleukin-1α (IL-1α), and tumor necrosis factor β (TNF-β) as well as the chemokines, monocyte chemotactic protein 1 (MCP-1), and chemokine (C-X-C motif) ligand 1 protein (CXCL1). Additionally, we found that LCZ696 reduces LPS-induced expressions of vascular cell adhesion molecule 1 (VCAM-1) and P-selectin and the attachment of U937 monocytes to HUVECs. Mechanistically, LCZ696 prevents LPS-induced activation of the TLR4/Myd88 pathway and nuclear translocation of nuclear factor kappa-B (NF-κB) p65 factor. Based on these findings, we conclude that LCZ696 is capable of ameliorating LPS-induced endothelial dysfunction via anti-inflammatory properties.

Sacubitril/valsartan alleviates sepsis‐induced acute lung injury via inhibiting GSDMD‐dependent macrophage pyroptosis in mice

“…Interestingly, the potential impact of SV has not been reported in sepsis or acute lung injury. Though the anti-inflammatory effect of SV has been defined in LPS-induced endothelial injury, the role of SV in sepsis remains unknown [34]. In our study, we established that the effect of SV was related to its inhibition of pyroptosis, and we used GSDMD À/À mice to verify the important role of GSDMD in ALI mice.…”

“…The ARBs are well established to have profound antiinflammatory properties [26]. Thus, we administered the same doses of SV, valsartan, losartan, azilsartan, candesartan, irbesartan and telmisartan (10 lM) to lipopolysaccharide (LPS)-stimulated bone marrowderived macrophages (BMDMs) to compare the potential effects of SV and commonly used clinical ARBs [26,33,34]. ARBs treatment led to varying degrees of reduction in mRNA expression of various inflammatory cytokines, including IL-1b, IL-6, TNF-a, CCL7, CCL2, CXCL1, CXCL2 and CXCL10 compared to LPS alone.…”

Serum vimentin predicts mortality in pediatric severe sepsis: A prospective observational study

“…In the current study, serum vimentin levels were positively correlated with serum P-selectin levels. The levels of P-selectin, a well-known indicator for endothelial cell injury, significantly increased in sepsis and after LPS dose administration ( Gao, 2021 ;van Poelgeest et al, 2018 ;Zonneveld et al, 2014 ). Therefore, high serum vimentin levels could be an indicator for endothelial injury in sepsis.…”

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

“…Furthermore, atherosclerotic plaque area and lipid content were reduced, collagen content and fibrous cap thickness were increased, and plaque stability was improved ( 19 ). Sacubitril/valsartan downregulates the expression of pro-inflammatory cytokines IL-6, IL-1α, tumor necrosis factor (TNF-β), chemokine (MCP-1), and chemokine CXC motif ligand-1 (CXCL1) by inhibiting the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (Myd88) pathway, NF-κB p65 nuclear translocation, and improving lipopolysaccharide (LPS)-induced endothelial cell inflammation ( 20 ). It significantly reduces circulating TNF-α and IL-18 levels in patients with HF with reduced ejection fraction (HFrEF) after 4 weeks of treatment, accompanied by improved peripheral vascular function and increased exercise tolerance ( 21 ).…”