Discovery of shear-and side-specific mRNAs and miRNAs in human aortic valvular endothelial cells

Casey J. Holliday, Randall F. Ankeny, Hanjoong Jo*, Robert M. Nerem

*Corresponding author for this work

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

The role of endothelial cells (ECs) in aortic valve (AV) disease remains relatively unknown; however, disease preferentially occurs in the fibrosa. We hypothesized oscillatory shear (OS) present on the fibrosa stimulates ECs to modify mRNAs and microRNAs (miRNAs) inducing disease. Our goal was to identify mRNAs and miRNAs differentially regulated by OS and laminar shear (LS) in human AVECs (HAVECs) from the fibrosa (fHAVECs) and ventricularis (vHAVECs). HAVECs expressed EC markers as well as some smooth muscle cell markers and functionally aligned with the flow. HAVECs were exposed to OS and LS for 24 h, and total RNA was analyzed by mRNA and miRNA microarrays. We found over 700 and 300 mRNAs down-and upregulated, respectively, by OS; however, there was no side dependency. mRNA microarray results were validated for 26 of 28 tested genes. Ingenuity Pathway Analysis revealed thrombospondin 1 (Thbs1) and NF-κB inhibitor-α (Nfkbia) as highly connected, shear-sensitive genes. miRNA array analysis yielded 30 shear-sensitive miRNAs and 3 side-specific miRNAs. miRNA validation confirmed 4 of 17 shear-sensitive miRNAs and 1 of 3 side-dependent miRNAs. Using miRWalk and several filtering steps, we identified shear-sensitive mRNAs potentially targeted by shear-sensitive miRNAs. These genes and signaling pathways could act as therapeutic targets of AV disease.

Original languageEnglish (US)
Pages (from-to)H856-H867
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume301
Issue number3
DOIs
StatePublished - Sep 2011

Keywords

  • Aortic valve
  • Endothelium
  • MicroRNA
  • Microarray
  • Shear stress

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Discovery of shear-and side-specific mRNAs and miRNAs in human aortic valvular endothelial cells'. Together they form a unique fingerprint.

  • Cite this