Abstract 375: Fatty Acid Oxidation Inhibition Reverses Pulmonary Hypertension; A Metabolic Basis For Vascular Remodeling
Pulmonary Arterial Hypertension (PAH) is characterized by resistance to apoptosis in the vascular media. Apoptosis resistance in cancer is associated with a specific metabolic phenotype, i.e. aerobic glycolysis. Dichloroacetate (DCA), an activator of the mitochondrial pyruvate dehydrogenase, which promotes glucose oxidation over glycolysis, induces vascular apoptosis and reverses PAH and cancer growth. DCA also reverses the inhibition of K+ channels that characterizes PAH, suggesting a mitochondrial-K+ channel axis. We hypothesized that the PAH vascular remodeling has a metabolic basis. We studied normoxic and chronically hypoxic wild-type (N-W and CH-W) vs mice lacking malonyl-CoA-decarboxylase (N-MCD-KO, CH-MCD-KO), a metabolic enzyme that when inhibited, suppresses mitochondrial fatty acid oxidation (FAO) and promotes glucose oxidation. Inhibition of FAO with trimetazidine (TMZ) was performed in CH-W mice and a rat model of PAH (monocrotaline, MCT). We measured PA pressure (in closed-chest mice), right ventricular hypertrophy, functional status (max distance in treadmill) and lung angiograms (micro-CT). In PA smooth muscle cells, we measured mitochondrial membrane potential (ΔΨ;m, using TMRM), superoxide production (using mitosox), K+ current (patch clamping) and intracellular Ca++ (Fura2 AM). There was no difference between N-W and N-MCD-KO mice. The CH-W mice developed PAH, had hyperpolarized ΔΨm, decreased mitochondrial superoxide, decreased Ik & membrane potential (Em) and increased Ca++. However, the CH-MCD-KO mice were resistant to PHT and not different from normoxic mice in any parameter tested (Table⇓). CH-W mice and MCT-PAH rats treated with TMZ for 2 weeks had improved PA pressure and vascular density and normalized ΔΨm, IK+ and Ca++ levels. We show for the first time a critical role of mitochondrial metabolism in PAH. As in cancer, resistance to apoptosis in PAH might have a metabolic basis, which could be therapeutically targeted.