Paeonol Attenuates LPS-Induced Endothelial Dysfunction and Apoptosis by Inhibiting BMP4 and TLR4 Signaling Simultaneously but Independently

Abstract

Inflammatory injury of the endothelium leads to apoptosis and endothelial dysfunction. The current study explored the effect and mechanisms of paeonol in inflammation-induced apoptosis and endothelial dysfunction induced by lipopolysaccharides (LPSs). The effects of paeonol on LPS-induced inflammatory injury were assessed by Western blotting, flow cytometry and reactive oxygen species (ROS) measurement in human umbilical vein endothelial cells (HUVECs) and C57BL/6J mice. Vascular reactivity of isolated mouse aortae was examined using wire myographs. The exposure of HUVECs to LPS increased the protein presence of Toll-like receptor 4 (TLR4), bone morphogenic protein 4 (BMP4), BMP receptor type 1A, nicotinamide adenine dinucleotide phosphate oxidase subunit 2, mitogen-activated protein kinase (MAPK), inducible nitric oxide synthase (iNOS), and cleaved caspase 3, as well as decreased it in phosphorylated endothelial nitric oxide synthase; these effects were prevented by treatment with paeonol. Similarly, cotreatment with paeonol reversed BMP4-induced apoptosis in HUVECs. Relaxation in response to the endothelium-dependent vasodilator acetylcholine were impaired in mouse aortae after exposure to LPSs; this endothelial dysfunction was reversed by cotreatment with paeonol, noggin (a BMP4 inhibitor), TAK242 (TLR4 antagonist), apocynin (an ROS scavenger), MAPK inhibitors, and AG (an iNOS inhibitor). BMP4 small interfering RNAs (siRNAs) abolished LPS-induced upregulation of BMP4 and cleaved caspase 3 protein, but not in cells treated with TLR4 siRNA and vice versa. The silencing of TLR4 and BMP4 abolished the inhibitory effects of paeonol on LPS-induced activation of cleaved caspase 3. The present results demonstrate that paeonol reduces LPS-induced endothelial dysfunction and apoptosis by inhibiting TLR4 and BMP4 signaling independently.

Genetic Influences on the Amount of Cell Death in the Neural Tube of BXD Mice Exposed to Acute Ethanol at Midgestation

“…Ptger2 has been shown to play a role in both cell survival and apoptosis (Fu et al., ; Jonakait and Ni, ; Liou et al., ). Interestingly, another gene, Bmp4 , has also been implicated in FASD as a mediator of apoptosis in multiple regions of the embryo and also exerts pro‐inflammatory effects that can result in cell death (Choy et al., ; Kennelly et al., ; Trousse et al., ; Zhang et al., ).…”

A Synthetic Peptide AWRK6 Alleviates Lipopolysaccharide-Induced Liver Injury

“…LPS could interact with LPS-binding protein (LBP) and initiate intracellular signaling through Toll-like receptor 4 (TLR4), which could active different signals, such as MAPKs and NFκB, leading to cell apoptosis and the secretion of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α [ 13 , 14 , 32 , 33 ]. The MAPKs are a group of serine-threonine protein kinases playing important roles in extracellular signaling transduction to regulate cell proliferation, differentiation and apoptosis [ 34 ].…”

Cynanchum paniculatum and Its Major Active Constituents for Inflammatory‐Related Diseases: A Review of Traditional Use, Multiple Pathway Modulations, and Clinical Applications

“…It is worth noting that the anti-inflammatory and antioxidative activities of paeonol and its metabolites were found mostly through blocking MAPK/ERK/p38 signaling pathway and PI3K/Akt/NF- κ B pathway [ 27 , 40 , 41 ]. A recent study also suggests paeonol attenuates LPS-induced endothelial dysfunction and apoptosis by inhibiting bone morphogenetic protein 4 (BMP4) and TLR4 signaling independently [ 42 ]. Further study may provide further understanding to inflammatory disease and broadened the application of Cynanchum paniculatum and its derivatives.…”