Sirtuin 3 deficiency does not augment hypoxia-induced pulmonary hypertension

Gregory B. Waypa, Scott W. Osborne, Jeremy D. Marks, Sara K. Berkelhamer, Jyothisri Kondapalli, Paul T. Schumacker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Alveolar hypoxia elicits increases in mitochondrial reactive oxygen species (ROS) signaling in pulmonary arterial (PA) smooth muscle cells (PASMCs), triggering hypoxic pulmonary vasoconstriction. Mice deficient in sirtuin (Sirt) 3, a nicotinamide adenine dinucleotide-dependent mitochondrial deacetylase, demonstrate enhanced left ventricular hypertrophy after aortic banding, whereas cells from these mice reportedly exhibit augmented hypoxia-induced ROS signaling and hypoxia-inducible factor (HIF)-1 activation. We therefore tested whether deletion of Sirt3 would augment hypoxia-induced ROS signaling in PASMCs, thereby exacerbating the development of pulmonary hypertension (PH) and right ventricular hypertrophy. In PASMCs from Sirt3 knockout (Sirt3-/-) mice inthe C57BL/6 background,weobserved that acute hypoxia(1.5% O 2;30min)-induced changes in ROS signaling, detected using targeted redox-sensitive, ratiometric fluorescent protein sensors (roGFP) in the mitochondrial matrix,intermembranespace,andthecytosol,wereindistinguishable from Sirt3+/+ cells. Acutehypoxia-inducedcytosolic calcium signaling in Sirt3-/- PASMCs was also indistinguishable from Sirt3+/+ cells. During sustained hypoxia (1.5% O2; 16 h), Sirt3 deletion augmented mitochondrial matrix oxidant stress, but this didnot correspondtoan augmentationofintermembranespaceorcytosolicoxidantsignaling. Sirt3 deletion did not affect HIF-1α stabilization under normoxia, nor did it augment HIF-1α stabilization during sustained hypoxia (1.5% O2; 4 h). Sirt3-/- mice housed in chronic hypoxia (10% O2; 30 d) developed PH, PA wall remodeling, and right ventricular hypertrophy that was indistinguishable from Sirt3+/+ littermates. Thus, Sirt3deletiondoesnotaugmenthypoxia-induced ROS signaling or its consequences in the cytosol of PASMCs, or the development of PH. These findings suggest that Sirt3 responses may be cell type specific, or restricted to certain genetic backgrounds.

Original languageEnglish (US)
Pages (from-to)885-891
Number of pages7
JournalAmerican journal of respiratory cell and molecular biology
Volume49
Issue number6
DOIs
StatePublished - Dec 2013

Keywords

  • Hypoxia-inducible factor-1
  • Hypoxic pulmonary vasoconstriction
  • Reactive oxygen species
  • Redox-sensitive, ratiometric fluorescent protein sensor
  • Sirtuins

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Fingerprint Dive into the research topics of 'Sirtuin 3 deficiency does not augment hypoxia-induced pulmonary hypertension'. Together they form a unique fingerprint.

Cite this