RT Journal Article
SR Electronic
T1 Right heart hypertrophy in mice deficient of the mitochondrial regulator protein p66shc is decreased after chronic hypoxic exposure by a cyclophilin D dependent mechanism
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P2301
VO 44
IS Suppl 58
A1 Mareike Gierhardt
A1 Natascha Sommer
A1 Rolf Schreckenberg
A1 Klaus Dieter Schlueter
A1 Ardeschir H. Ghofrani
A1 Ralph T. Schermuly
A1 Schulz Rainer
A1 Weissmann Norbert
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/P2301.abstract
AB The mitochondrial protein p66shc enhances production of mitochondrial reactive oxygen species (ROS) in response to cellular stress, probably via the mitochondrial protein cyclophilin D (CypD). Mitochondrial ROS are suggested to regulate the response of the pulmonary vasculature to acute and chronic hypoxia. Thus we hypothesized that p66shc deficient mice produce less ROS and exhibit lower hypoxic pulmonary vasoconstriciton (HPV) and pulmonary hypertension (PH) in response to hypoxia.HPV was determined in isolated lungs of p66shc and CypD deficient mice, as well as mice lacking both proteins, and compared to wild type (WT) mouse lungs. The thromboxane mimetic U46619 and potassium chloride were used as hypoxia-independent vasoconstrictive stimuli. PH was quantified after exposure of mice to 10% oxygen for 4 weeks by in vivo hemodynamics, and morphometric analysis.Mice deficient of p66shc exhibited lower HPV compared to WT mice. The vasoconstrictive response to U46619, as well as potassium chloride was also decreased. After exposure to chronic hypoxia, p66shc deficient mice exhibited lower right ventricular pressure, right ventricular hypertrophy and hematocrit, but unchanged vascular remodeling, compared to WT mice. In mice lacking CypD or both proteins, no significant changes of these parameters in chronic hypoxia were detected, although the response to acute hypoxia and vasoconstrictive stimuli were also attenuated compared to WT mice.The mitochondrial ROS producing protein p66shc regulates right heart hypertrophy and right ventricular pressure during chronic hypoxia, probably via a CypD dependent mechanism.