15 February 2020 by Mareike Gierhardt

The mitochondrially located proteins p66shc and cyclophilin D are contributing to the regulation of the pulmonary vascular tone

vascular functions, in particular the response of the pulmonary vasculature to hypoxia. We investigated whether the proteins p66shc and cyclophilin D (CypD), which regulate release of mitochondrial reactive oxygen species and apoptosis, may influence pulmonary vascular functions. Mice deficient for p66shc (p66shc-/-), CypD (CypD-/-), or both proteins (p66shc/CypD-/-) exhibited a lower pulmonary vascular resistance compared to wildtype (WT) mice determined in vivo by hemodynamic measurements and in isolated lungs. Systemic arterial pressure was, however, only lower in CypD-/- mice. Pulmonary vasoconstriction and intracellular calcium increase induced by KCl was lower in the lungs or pulmonary arterial smooth muscle cells from gene deficient compared to WT mice. However, cardiac function and pulmonary vascular morphometric parameters did not differ. All mouse strains showed a similar response to chronic hypoxia with regard to development of pulmonary hypertension.

We conclude that p66shc specifically regulates the pulmonary vascular tone, while CypD also affects systemic blood pressure. The pulmonary effects can be explained by decreased pulmonary vasoconstriction, suggested to be caused by p66shc and CypD interfering with the intracellular calcium homeostasis. As the observed differences were not additive in the p66shc/CypD-/- double ko mice, p66shc and CypD most likely act via similar pathways. p66shc thus may be a new candidate for targeting pulmonary vascular disease.

This work was funded by Deutsche Forschungsgemeinschaft Grant SFB1213, Project A06 and B05 (NW, NS, RS).

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Mareike Gierhardt




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Key Contributors

Mareike Gierhardt, Julia Schäffer, Oleg Pak, Akylbek Sydykov, Karin Quanz, Azadeh Esfandiary, Jochen Wilhelm, Hossein A. Ghofrani, Ralph T. Schermuly, Werner Seeger, Friedrich Grimminger, Christiane Herden, Rainer Schulz, Norbert Weissmann, Natascha Sommer Excellence Cluster Cardiopulmonary System (ECCPS), University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany Institute of Veterinary Pathology, Justus Liebig University, Giessen, Germany Institute of Physiology, Justus Liebig University, Giessen, Germany

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