Investigating the role of coiled-coil domain containing protein 3 (CCDC3), a novel secreted protein, in endothelial inflammation

• Author / Creator

  Azad, Abul K

• Endothelial inflammation is critical in the initiation and progression of atherosclerosis and other cardiovascular diseases (CVDs). Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine that induces endothelial inflammation via activation of nuclear factor κB (NF-κB) signaling. Coiled-coil domain containing 3 (CCDC3) is a newly identified secretory protein mainly expressed in endothelial cells (ECs) and in adipose tissues. However, the function of CCDC3 in ECs is unclear. A published paper showed that TNF-α downregulates CCDC3 expression in ECs. We therefore investigated the role of CCDC3 in TNF-α-induced inflammatory response in ECs.
  In response to inflammation, ECs express adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1) that recruit leukocytes to the sites of infection or injury. In our study we found that stable overexpression of CCDC3 decreased, while stable knockdown of CCDC3 increased TNF-α-induced expression of VCAM-1 at the mRNA and protein levels in ECs. Mechanistically, stable overexpression of CCDC3 decreased TNF-α-induced p65 and p50 nuclear translocation and nuclear NF-κB activity, suggesting that CCDC3 attenuates TNF-α-induced gene expression by inhibiting NF-κB signaling in ECs. Importantly, we found that CCDC3 in the conditioned medium (CM) as well as the purified CCDC3 decreased TNF-α-induced expression of VCAM-1 in receiving ECs, suggesting that CCDC3 has a paracrine/autocrine function. Interestingly, CCDC3 in CM can enter the receiving ECs. Taken together, our work demonstrates that CCDC3 represses TNF-α/NF-κB-induced pro-inflammatory response in ECs, suggesting a potential anti-inflammatory and atheroprotective role of CCDC3 in vascular ECs.

• Subjects / Keywords

  • Atherosclerosis
  • TNF
  • VCAM-
  • HUVEC
  • NF-kB
  • HMEC
  • Inflammation

• Graduation date

  Fall 2015

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R3B27Q03F

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.