Author + information
- Christian Pfluecke,
- Marian Christoph,
- Karim Ibrahim,
- Matthias Mensch,
- Peggy Barthel,
- Kristin Franke,
- Ben Wielockx,
- Ruth H. Strasser,
- Carsten Wunderlich and
- David M. Poitz
Prolylhydroxylase Domain Protein 2 (PHD–2) acts as oxygen sensor and is responsible for the O2–dependent destabilisation of the hypoxia–inducible factor (HIF) α subunit. In this study, the possible anti–atherogenic potential of PHD2 was focused. Therefore, LysMcrePHD2–flox/flox/Hif1α–flox/flox double knockout mice [PHD2/Hi1α–ko] were compared to the LysMcrePHD2–flox/flox [PHD2–ko] and the respective wildtypes. As surface receptor expression on monocytes and granulocytes seems to play a crucial role in the myeloid PHD2–dependent atherosclerosis progression, important adhesion molecules MAC–1, PSGL–1 and VLA–4 were focussed as well.
The induction of atherosclerotic plaques in mice was done by a guide wire induced endothelial injury of the A.femoralis. The extend of plaque development was quantified by determining the intima–media–ratio at 5 weeks. Expression of the adhesion molecules MAC–1, PSGL–1 and VLA–4 were determined by FACS–analysis either from PHD2–ko mice or from PHD2/Hif1α–ko mice in comparison with their wild type littermates 5 days after denudation.
PHD2–ko mice showed a remarkable enhanced plaque progression with significantly increased intima–media–(3fold) compared to wild type mice. Myeloid–specific conditional knockout of PHD2 and Hif–1α led to significantly reduced intima–media ratios compared to PHD2–knockouts (70 % reduction). Responsible for this Hif–dependent effect might be the expression of adhesion molecules. PHD2–ko mice showed an increased expression of MAC–1, PSGL–1 and VLA–4 on granulocytes as well as on monocytes. Interestingly, the additional knockout of Hif–1α in PHD2–deficient mice abolished this increased expression.
This study demonstrates that myeloid–specific PHD–2 knockout in mice promotes plaque progression. Furthermore, PHD2–ko led to enhanced adhesion molecule expression on granulocytes and monocytes. By double knock–out strategy it could be revealed that the enhanced proatherogenic potential of PHD2–ko is dependent on Hif 1α as PHD2/Hif–1α–ko mice showed reduced atherosclerotic plaque development and reduced adhesion molecule expression on granulocytes and monocytes.
Poster Sessions, Expo North
Sunday, March 10, 2013, 3:45 p.m.–4:30 p.m.
Session Title: Preclinical and Translational Research
Abstract Category: 52. TCT@ACC–i2: Translation and Pre–clinical Research
Presentation Number: 2111–241
- 2013 American College of Cardiology Foundation