(556.27) A Cell Permeant Phosphopeptide Mimetic Of Niban Restores Endothelial Function And Inhibits p38 MAPK Activation After IL-1β Induced Vascular Injury

Poster Board Number: E119

Anish Katta (Vanderbilt University Medical Center), Amanda Sisung (Vanderbilt University Medical Center), Madeleine Morelli (Vanderbilt University Medical Center), Colleen Brophy (Vanderbilt University Medical Center), Joyce Cheung-Flynn (Vanderbilt University Medical Center)

Activation and dysfunction of the vascular endothelium play a significant role in the pathogenesis of many viral infections such as COVID-19. The cytokine storm (systemic inflammation) present in COVID-19 causes organ failure by inflaming the vascular endothelium, leading to endothelial dysfunction and eventually death. Previous studies in the laboratory show that vascular injury leads to endothelial dysfunction that is associated with activation of p38 MAPK signaling and altered phosphorylation of Niban. Based on these findings, a cell permeant phosphomimetic peptide of Niban (NiPp) was developed and shows inhibitory activities on p38 MAPK and restores endothelial dysfunction after vascular injury.  The effects of NiPp on endothelial dysfunction induced by interleukin-1β (IL-1β), a cytokine that is increased during infections, were examined ex-vivo using intact rat aortic tissue (RA) and primary human endothelial cells (HCAEC). IL-1β treatment led to a reduction in endothelial-dependent relaxation (EDR) in RA, and inhibition of p38 MAPK by NiPp or BIRB796, a potent p38 MAPK inhibitor, improved EDR in IL-1β treated RA (Figure 1). Treatment of HCAEC with NiPp or BIRB reduced IL-1β induced activation of p38 MAPK and its downstream substrate, CREB (Figure 2). These data show that p38 MAPK and Niban signaling play a role in endothelial function, especially in response to inflammatory injury. Niban may be an endogenous regulator of p38 MAPK activation. NiPp may serve as a potential therapeutic to ameliorate inflammation of vascular endothelium.

This work was supported by the National Institutes of Health grant R01HL70715-09





Figure 1.  NiPp restored interleukin-1β mediated endothelial dysfunction in rat aorta (RA). RA was incubated in the absence or presence of NiPp (100µM) or BIRB796 (5uM) for 2hr. Endothelial-dependent relaxation to carbachol (CCH) was determined in the muscle bath. n=6 rats; *p <.05 vs IL-1β, two-way ANOVA with Tukey post-tests (p <.05 at all CCH doses).; Figure 2: NiPp inhibited interleukin-1β induced phosphorylation of p38 MAPK and CREB in primary human endothelial cells (HCAEC).  HCAEC, were treated with IL1β (10ng/ml) for 30min and cell lysates were immunoblotted for p38 MAPK and CREB. n=3-7 from 2 donors, *p <.05 in one-way ANOVA with Tukey post-tests