Abstract: FR-PO212

Characterization of a Novel β-Common Receptor Inhibitory Peptide

Session Information

Category: Hypertension

  • 1103 Vascular Biology and Dysfunction

Authors

  • Kilar, Cody, University of Florida, GAINESVILLE, Florida, United States
  • Diao, Yanpeng, University of Florida , Gainesville, Florida, United States
  • Keinan, Shahar, Cloud Pharmaceuticals, RTP, North Carolina, United States
  • Shen, Yong, University of Florida , Gainesville, Florida, United States
  • Bungert, Jorg, University of Florida , Gainesville, Florida, United States
  • Mohandas, Rajesh, University of Florida, GAINESVILLE, Florida, United States
  • Segal, Mark S., University of Florida, GAINESVILLE, Florida, United States
Background

In short term animal models of ischemia, erythropoietin (EPO) signaling through the heterodimeric EPO receptor/β-common receptor (βCR) is believed to elicit tissue protective effects. However, large randomized controlled trials demonstrate that administering high doses of EPO, which can activate the βCR, is associated with an increase in adverse cardiovascular events. Thus, inhibition of the βCR may have therapeutic implications. This study aimed to design and evaluate the efficacy of a novel computationally designed βCR inhibitory peptide (βIP).

Methods

The novel βIP was designed from the crystal structure of EPO consisting of 16-amino acids (VLERYLLEAKEAEKIT) from residues 11 to 26. Ultimately, the 16-amino acid peptide model comprising of VLERYLHEAKHAEKIT, was selected as a novel βIP. The efficacy of βIP to inhibit βCR-induced nitric oxide (NO) production and angiogenesis in human umbilical vein endothelial cells (HUVECs) was evaluated.

Results

We found that βIP completely abolished EPO-induced NO production, however could be overcome with super physiological doses of EPO. βCR-induced angiogenesis in HUVEC’s was also abolished with treatment of βIP, but βIP did not inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis. In addition, we show that the novel βIP does not increase erythropoiesis or inhibit EPO-induced erythropoiesis with use of peripheral blood mononuclear cells (PBMCs).

Conclusion

These results introduce, for the first time, a novel, potent βCR inhibitor that inhibit the actions of the βCR without affecting erythropoiesis. Experiments addressing the therapeutic use of this peptide will be discussed.

Funding

  • Other NIH Support