Abstract 14667: Endothelial-specific Loss of Primary Cilia Exacerbates Cardiac Fibrosis
Introduction: Cardiac fibrosis after injury, which significantly compromises heart function, is in part due to proliferation of fibroblasts of unclear cellular origin. Primary cilia are cellular protrusions that serve as mechanosensors for fluid flow. Loss of endothelial cilia coincides with endothelial-mesenchymal transition (EndMT), however the driving mechanism linking endothelial cilia and cardiac fibrosis remain mainly unexplored
Methods: To elucidate the involvement of endothelial cilia in cardiac fibrosis in vivo and in vitro, we generated endothelial cell-specific Ift88-knockout mice (Ift88endo) and silenced Ift88 in human coronary artery endothelial cells (HCAECs), respectively to evaluate EndMT and fibrosis.
Results: Silencing of Ift88 in HCAECs resulted in loss of endothelial cilia. A microscopic evaluation revealed mesenchymal cells-like morphological and ultra-structural changes in Ift88-silenced cells. Expression of endothelial markers, CD31, Tie-2 and VE-cadherin, were significantly low with significant increase in mesenchymal markers, αSMA, N-cadherin and FSP-1 in Ift88-silenced HCAECs. We also observed enhanced expression and activation of Tgfβ1, its receptors TGFBR1/2 and effectors SMAD2/3 as well as enhanced transcription of the pro-fibrotic genes collagen-I and CTGF. Tgfβ1 exposure further exacerbated Tgfβ-signaling and EndMT in Ift88-silenced HCAECs. We also detected increased Wnt/β-catenin signaling in Ift88-silenced HCAECs. In vivo, loss of Ift88 in endothelial cells isolated from the hearts of Ift88endo mice demonstrated reduced endothelial markers CD31 and VE-cadherin, and increased expression of the mesenchymal markers αSMA, N-cadherin, collagen-I and FSP-1 under basal conditions. Ift88endo mice demonstrated normal cardiac function at baseline but aortic banding induced excess cardiac fibrosis and mortality amongst Ift88endo mice compared to control mice.
Conclusions: Our findings demonstrate the role of endothelial cilia and associated signaling in cardiac fibrosis and may provide a potential therapeutic target to limit cardiac fibrosis, for which presently there are no effective treatments available.
Author Disclosures: K.K. Singh: None. P.N. Matkar: None. J.W. Yau: None. Y. Pan: None. A. Quan: None. J. Desjardines: None. T.G. Parker: None. M. Al-Omran: None. S. Verma: None.
- © 2016 by American Heart Association, Inc.