Ac-SDKP suppresses TNF-α-induced ICAM-1 expression in endothelial cells via inhibition of IκB kinase and NF-κB activation

Abstract

Zhu L, Yang X-P, Janic B, Rhaleb N-E, Harding P, Nakagawa P, Peterson EL, Carretero OA. Ac-SDKP suppresses TNF-␣-induced ICAM-1 expression in endothelial cells via inhibition of IB kinase and NF-B activation. Am J Physiol Heart Circ Physiol 310: H1176 -H1183, 2016. First published March 4, 2016 doi:10.1152/ajpheart.00252.2015.-N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide that prevents inflammation and fibrosis in hypertension and other cardiovascular diseases. We previously showed that, in angiotensin II-induced hypertension, Ac-SDKP decreased the activation of nuclear transcription factor NF-B, whereas, in experimental autoimmune myocarditis and hypertension animal models, it also reduced the expression of endothelial leukocyte adhesion molecule ICAM-1. However, the mechanisms by which Ac-SDKP downregulated ICAM-1 expression are still unclear. TNF-␣ is a proinflammatory cytokine that induces ICAM-1 expression in various cell types via TNF receptor 1 and activation of the classical NF-B pathway. We hypothesized that in endothelial cells Ac-SDKP suppresses TNF-␣-induced ICAM-1 expression by decreasing IKK phosphorylation that as a consequence leads to a decrease of IB phosphorylation and NF-B activation. To test this hypothesis, human coronary artery endothelial cells were treated with Ac-SDKP and then stimulated with TNF-␣. We found that TNF-␣-induced ICAM-1 expression was significantly decreased by Ac-SDKP in a dose-dependent manner. Ac-SDKP also decreased TNF-␣-induced NF-B translocation from cytosol to nucleus, as assessed by electrophoretic mobility shift assay, which correlated with a decrease in IB phosphorylation. In addition, we found that Ac-SDKP decreased TNF-␣-induced IKK phosphorylation and IKK-␤ expression. However, Ac-SDKP had no effect on TNF-␣-induced phosphorylation of p38 MAP kinase or ERK. Thus we conclude that Ac-SDKP inhibition of TNF-␣ activation of canonical, i.e., IKK-␤-dependent, NF-B pathway and subsequent decrease in ICAM-1 expression is achieved via inhibition of IKK-␤.

Geniposide reduces development of streptozotocin‐induced diabetic nephropathy via regulating nuclear factor‐kappa B signaling pathways

“…In diabetic rats, ICAM‐1 expression was obviously increased as compared with that in normal rats ( Figure b , P < 0.05), and meanwhile, we also noted that in GPO‐treated diabetic rats, ICAM‐1 expression was significantly reduced ( Figure c, d , P < 0.05). Finally, considering expression of ICAM‐1 is induced by stimulation of inflammatory cytokine , we further measured production of TNF‐α, IL‐1, and IL‐6. The results showed GPO effectively reduced renal expression of TNF‐α, IL‐1, and IL‐6 as shown in Figure a – c ( P < 0.05).…”

The Absence of the ACE N-Domain Decreases Renal Inflammation and Facilitates Sodium Excretion during Diabetic Kidney Disease

“…62 Many of the beneficial effects of AcSDKP are mediated through the inhibition of TGF-b-related intracellular signaling pathways such as the transcription factors Smads. 63 In addition, AcSDKP inhibits the key proinflammatory transcriptional factor, NFkB 64 ; reduces the mRNA levels of TNF-a and IL-1b 65 ; and exerts a renal protective effect in Dahl salt-sensitive rats. 66 Thus, the increased sodium excretion observed in diabetic NKO mice might be mediated through the anti-inflammatory effects of AcSDKP.…”

Angiotensin-converting enzyme in innate and adaptive immunity

“…As a result, most angiotensin I is cleaved by the C-terminal domain in vivo 99 . By contrast, other peptides, such as the immunosuppressive peptide acetyl-SDKP, are cleaved by the N-terminal domain in vivo 100,101 .…”