| First Author | Wu X | Year | 2022 |
| Journal | Pharmacol Res | Volume | 175 |
| Pages | 106043 | PubMed ID | 34954030 |
| Mgi Jnum | J:341284 | Mgi Id | MGI:7431020 |
| Doi | 10.1016/j.phrs.2021.106043 | Citation | Wu X, et al. (2022) Pharmacological inhibition of IRAK1 and IRAK4 prevents endothelial inflammation and atherosclerosis in ApoE(-/-) mice. Pharmacol Res 175:106043 |
| abstractText | Inflammation associated endothelial dysfunction represents a pivotal contributor to atherosclerosis. Increasingly, evidence has demonstrated that interleukin 1 receptor (IL1-R) / toll-like receptor (TLR) signaling participates in the development of atherosclerosis. Recent large-scale clinical trials have supported the therapeutic potential of anti-inflammatory therapies targeting IL-1beta and IL-6 in reducing atherosclerosis. The present study examined the pharmacological effects of IL-1R-associated kinase 1 and 4 inhibitors (IRAK1/4i) in regulating inflammation of the endothelium and atherosclerosis. We demonstrate that dual pharmacological inhibition of IRAK1 and IRAK4 by an IRAK1/4i is more effective against LPS induced endothelial inflammation, compared with IRAK1 inhibitor or IRAK4 inhibitor monotherapy. IRAK1/4i showed little endothelial cell toxicity at concentrations from 1 muM up to 10 muM. Inhibition of IRAK1/4 reduced endothelial activation induced by LPS in vitro as evidenced by attenuated monocyte adhesion to the endothelium. Mechanistically, blockade of IRAK1/4 ameliorated the transcriptional activity of NF-kappaB. To assess the pharmacological effects of IRAK1/4i on atherosclerosis in vivo, ApoE(-/-) mice were orally administered IRAK1/4i (20 mg/kg/d) for 8 weeks. We show that IRAK1/4i reduced atherosclerotic lesion size in the aortic sinus and increased hepatic LDLR protein levels as well as lowered LDL-C level, without affecting other lipid parameters or glucose tolerance. Taken together, our findings demonstrate that dual pharmacological inhibition of IRAK1 and IRAK4 attenuates endothelial inflammation, lowers LDL-C levels and reduces atherosclerosis. Our study reinforces the evolving standing of anti-inflammatory approaches in cardiovascular therapeutics. |
