PUBLICATION
Cilia proteins are biomarkers of altered flow in the vasculature
- Authors
- Gupta, A., Thirugnanam, K., Thamilarasan, M., Mohieldin, A.M., Zedan, H.T., Prabhudesai, S., Griffin, M.R., Spearman, A.D., Pan, A., Palecek, S.P., Yalcin, H.C., Nauli, S.M., Rarick, K.R., Zennadi, R., Ramchandran, R.
- ID
- ZDB-PUB-220211-10
- Date
- 2022
- Source
- JCI insight 7(6): (Journal)
- Registered Authors
- Ramchandran, Ramani
- Keywords
- Endothelial cells, Molecular diagnosis, Vascular Biology
- MeSH Terms
-
- Animals
- Biomarkers/metabolism
- Cilia*/metabolism
- Endothelial Cells/metabolism
- Humans
- Mammals
- Proteins/metabolism
- Reactive Oxygen Species/metabolism
- Zebrafish*
- PubMed
- 35143420 Full text @ JCI Insight
Citation
Gupta, A., Thirugnanam, K., Thamilarasan, M., Mohieldin, A.M., Zedan, H.T., Prabhudesai, S., Griffin, M.R., Spearman, A.D., Pan, A., Palecek, S.P., Yalcin, H.C., Nauli, S.M., Rarick, K.R., Zennadi, R., Ramchandran, R. (2022) Cilia proteins are biomarkers of altered flow in the vasculature. JCI insight. 7(6):.
Abstract
Cilia, microtubule-based organelles that project from the apical luminal surface of endothelial cells (ECs), are widely regarded as a low flow-sensors. Previous reports suggest that upon high shear stress, cilia on the EC surface are lost, and more recent evidence suggests that deciliation - the physical removal of cilia from the cell surface - is a predominant mechanism for cilia loss in mammalian cells. Thus, we hypothesized that EC deciliation facilitated by changes in shear stress will manifest in increased abundance of cilia-related proteins in circulation. To test this hypothesis, we performed shear stress experiments that mimicked flow conditions from low to high shear stress in human primary cells and a zebrafish model system. In the primary cells, we showed that upon shear stress induction, indeed, ciliary fragments were observed in the effluent in vitro and effluents contained ciliary proteins normally expressed in both endothelial and epithelial cells. In zebrafish, upon shear stress induction, fewer ciliary-expressing ECs were observed. To test the translational relevance of these findings, we investigated our hypothesis using patient blood samples from sickle cell disease and found that plasma levels of ciliary proteins were elevated compared to healthy controls. Further, sickled red blood cells demonstrated high levels of ciliary protein (Arl13b) on their surface post-adhesion to brain ECs. Brain ECs post interaction with sickle RBCs show high reactive oxygen species (ROS) levels. Attenuating ROS levels in brain ECs decreases cilia protein levels on RBCs and rescues ciliary protein levels in brain ECs. Collectively, these data suggest that cilia and ciliary proteins in circulation are detectable under various altered flow conditions, which could serve as a surrogate biomarker of the damaged endothelium.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping