Abstract 18830: Mitochondrial Suppression Due to Loss of Sirt3 Deacetylase Activity Causes Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by suppressed apoptosis in the pulmonary artery (PA) wall, leading to an obstructive vascular remodeling and premature death. The suppressed apoptosis is partly due to suppressed mitochondrial function. Recently PAH patients have been shown to have clinical evidence of insulin resistance. Sirtuin 3 (Sirt3), is a mitochondria-localized deacetylase that regulates mitochondrial function. Loss of Sirt3 activity promotes acetylation and inhibition of many mitochondrial enzymes, resulting in mitochondrial suppression. Loss-of-function polymorphisms in the SIRT3 gene have been associated with metabolic syndrome. We hypothesized that loss of SIRT3 promotes PAH. In vitro, we used resistance PA smooth muscle cells (PASMC) isolated from WT and KO SIRT3 mice. Normoxic-KO-PASMCs had a global decrease in Kreb’s cycle intermediates (mass spectrometry) and respiration, increased mitochondrial membrane potential and decreased mitochondrial reactive oxygen species compared to WT-PASMCs, mimicking the profile of WT-PASMC exposed to hypoxia. They also had activation of Hif-1a (luciferase activity assays), confirming a “pseudohypoxic” state, increased proliferation (%Ki67) and suppressed apoptosis (%TUNEL). In vivo, compared to WT, Sirt3 KO normoxic mice developed spontaneous PAH (mPAP, 30.9±3.13mmHg vs 14±1.41mmHg) which did not worsen by chronic-hypoxia CH (10% for 3 weeks), associated with right ventricle hypertrophy and significant vascular remodeling. Systemic blood pressures did not differ between groups. In the monocrotaline MCT rat model, intra-tracheal nebulization of Sirt3 adenovirus at day 21-post MCT injection, improved mPAP and vascular remodeling compared to the GFP-only adenovirus treated rats. We showed for the first time a critical role of SIRT3 in PAH. In a parallel abstract submission (Gurtu et al) we describe increased frequency of a characterized loss-of-function SIRT3 single nucleotide polymorphism in PAH patients. The loss of SIRT3 function causes a mitochondrial suppression perhaps explaining both the anti-apoptotic diathesis in PAH vessels and the extra-pulmonary metabolic abnormalities recently described in these patients.

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