Abstract 12388: Impaired Mitochondrial Bioenergetics is Associated With Progression of Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

Abstract

Introduction: Pulmonary arterial hypertension (PAH) has poor prognosis related to right ventricular (RV) dysfunction and failure. Yet, the underlying mechanisms of RV dysfunction remain unclear. Mitochondrial (mito) dysfunction and energy deficiency in RV have been implicated in RV dysfunction in PAH. A better understanding of RV mito function in PAH is critical in identifying novel therapies to improve RV function. Hypothesis: We hypothesized that impaired RV mito bioenergetics is associated with progression of RV dysfunction in PAH. Methods: PAH was induced in adult Sprague-Dawley (SD) or Fischer (CDF) rats by injecting 20 mg/kg SU5416, followed by exposure to 3 wks of hypoxia (10% FiO 2 ) and then 1-4 wks of normoxia. Control rats injected with vehicle were kept in normoxia. Echocardiography and hemodynamics were performed. RV tissues were collected for mito respiration assessments by high resolution O2K-FluoRespirometer (Oroboros), mito morphology assessments by electron microscopy, and biochemical assays. Results: PAH rats have increased RV systolic pressure, and RV systolic and diastolic dysfunction that ranged in severity from early PAH (1 wk SD), advanced PAH-mild to moderate RV dysfunction (7wks SD), to severe RV dysfunction (4 wks CDF - die of RV failure starting wk 5). Oroboros data show that mito complex I-coupled oxidative phosphorylation and maximal electron transfer capacity are significantly reduced in 7 wks SD rats (O 2 flux per mass: 216±21 vs. 90±19 and 209±22 vs. 91±22 pmol·s -1 ·mg -1 , respectively, control vs. PAH, P <0.01, N=6 each), which are further reduced in 4 wks CDF rats. In parallel, RV ATP amount is significantly lower in PAH rats and is associated with increased apoptosis. There are no changes in mito membrane integrity by cytochrome c assays or in mito content by PCR. Mito size analysis show a significant increase in smaller mito in 4 wks CDF rats but not in 7 wks SD rats, suggesting increased mito fission in severe RV dysfunction. Conclusions: RV mito bioenergetics is impaired in PAH, progressively worsens with progression of RV dysfunction, and occurs prior to increased mito fission. Targeting bioenergetics may aid in developing new therapies to improve mito function and delay RV failure in PAH.