Abstract 19386: The Mitochondrial Deacetylase Sirtuin 3 (sirt3) is Important in the Pathogenesis of Both Pulmonary Hypertension and Pulmonary Fibrosis: Potential for an “Overlap Syndrome” and a Common Therapy?

Introduction: Pulmonary arterial hypertension (PAH) is often associated with interstitial lung disease, like idiopathic pulmonary fibrosis (IPF). IPF pulmonary fibroblasts have a very similar pro-proliferative and anti-apoptotic phenotype similar to PAH vascular smooth muscle cells (SMC). As this phenotype is often associated with a cancer-like mitochondrial suppression, we hypothesized that a common mitochondria abnormality may underlie both PAH and IPF. We speculated that the loss of the mitochondrial deacetylase Sirt3, which we recently showed promotes PAH, will also promote IPF. Results: SIRT3 expression was decreased in human IPF-PH lungs (transplant recipients, n=7) and in Sirt3 wild type (Sirt3WT)+ bleomycin BLEO lungs (n=15 for each) and fibroblasts compared to healthy lungs (unused transplant tissue, n=3) and Sirt3WT. Sirt3 knockout (Sirt3KO) fibroblasts, like Sirt3WT+BLEO, had decreased mitochondrial function assessed by decreased pyruvate dehydrogenase activity, decreased respiration (Seahorse Assay) and increased mitochondrial membrane potential (TMRM dye in live cell imaging). Sirt3KO and Sirt3WT+BLEO fibroblasts had increased collagen production and smooth muscle actin expression (immunoblot). All of these findings are very similar to those in pulmonary artery SMCs from the same Sirt3KO animals, which develop spontaneous PAH. In vivo, Sirt3KO mice treated with BLEO developed worse IPF than Sirt3WT+BLEO (dynamic resistance 2±0.5 vs 1.4±0.2cmH2O.s/mL, dynamic elastance 20±3 vs 38±10cmH2O/mL). Intra-tracheal delivery of an adenovirus overexpressing SIRT3 improved both Sirt3KO+BLEO and Sirt3WT+BLEO compared to GFP-only adenovirus. We have previously showed that the same virus reverses PAH in rodents. Conclusion: Sirt3 downregulation plays an important role in the development of IPF. While the exact mechanisms by which Sirt3 is downregulated remains to be established, this work opens new perspectives for the treatment of IPF. Given the frequent overlap of IPF and pulmonary hypertension in the same patients, our data suggest the intriguing possibility that they both represent aspects of an “overlap syndrome”, which may benefit from similar therapeutic approaches, despite the differences in the “cell of origin”.

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