Abstract 19440: Dichloroacetate Fails to Improve Exaggerated Chronic-Hypoxia Induced Pulmonary Hypertension in Sirtuin 1 Mutant Mice
Background: Pulmonary Hypertension (PH) is caused by remodelling of pulmonary arterioles, leading to increased pulmonary vascular resistance, right ventricle hypertrophy and eventually heart failure. Sirtuin-1 (Sirt1) is an NAD+-dependent deacetylase strongly implicated in maintenance of endothelium homeostasis and metabolic balance. Our group has previously shown that both Sirt1 knockout and catalytic mutant mice exhibit exaggerated pulmonary hemodynamic response to chronic hypoxia (CH). Dichloroacetate (DCA) has been proposed to play a protective role in PH through inhibition of pyruvate dehydrogenase kinase, thus preventing glycolytic metabolic shift.
Hypothesis: Therefore, we posit that the increase response to CH in Sirt1 mutant mice is related to an increase in glycolytic metabolism that can be prevented by treatment with DCA.
Methods: Mice lacking Sirt1 catalytic activity (sirt1Y/Y, H355Y) and their wild type (WT) littermates were exposed to chronic hypoxia (CH; 10% O2) for 21 days with or without DCA in water at 75mg/kg/day.
Results: Absence of Sirt1 activity led to exaggerated increase in right ventricle systolic pressure (RVSP) at 3 weeks (40±1 sirt1Y/Y vs. 30±1 WT; n=39/group, p< 0.001) as well as significant right ventricular hypertrophy, assessed by the RV/LV+S weight ratio (0.55±0.01 sirt1Y/Y vs. 0.43±0.01 WT; n=39/group, p< 0.001) and increased hematocrit levels (71±1% sirt1Y/Y vs. 59±1% WT; n=24/group, p<0.001). Addition of DCA to the drinking water did not alter the hemodynamic response (RVSP: 34±3 WT; 40±3 sirt1Y/Y; n=4 and 7, respectively) or the severity of RV hypertrophy (0.44±0.06 WT; 0.51 ±0.03 sirt1Y/Y; n=4 and 7, respectively) in response to CH in Sirt1 mutant mice. Finally, DCA did not improve the CH-induced increase in hematocrit (60±2% WT; 65±3% sirt1Y/Y; n=4-5).
Conclusions: Loss of Sirt1 deacetylation activity led to an exaggerated pulmonary hemodynamic response to CH, consistent with a regulatory role for Sirt1 in hypoxia sensing and/or signaling. However, inhibition of glycolysis with DCA did not prevent the development of severe PH in mice lacking Sirt1 activity suggesting that metabolic shift does not contribute to potentiation of PH in this model of disease.
Author Disclosures: M. Taha: None. Y. Deng: None. M.W. McBurney: None. D.J. Stewart: None.
- © 2016 by American Heart Association, Inc.