Abstract 324: A Critical Role of Malonyl-CoA Decarboxylase in 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 (PDH) which inhibits glycolysis and promotes glucose oxidation, induces vascular apoptosis and reverses PAH. 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 wild (W) vs mice lacking malonyl-Co-Decarboxylase (MCD-KO), a mitochondrial enzyme inhibiting fatty acid oxidation. Inhibition of MCD also activates PDH, promoting glucose oxidation. We measured mean PA pressure (right heart catheterization in closed-chest mice), right ventricular hypertrophy, functional status (max distance covered in treadmill); in PA smooth muscle cells we measured mitochondrial membrane potential (ΔΨm, using TMRM), superoxide production (using mitosox), K+ current (whole-cell patch clamping) and intracellular Ca++ (fluo-3). There was no difference between W and MCD-KO mice at normoxia. After 3 week-hypoxia the W mice developed PAH, had hyperpolarized ΔΨm, decreased mitochondrial superoxide, decreased Ik & membrane potential (Em) and increased Ca++ However, the MCD-KO mice were completely resistant to PHT and were not different than normoxic mice (Table⇓). We describe for the first time the critical role of a mitochondrial enzyme, MCD, in the development of PAH. Like in cancer, the resistance to apoptosis in PAH might have a metabolic basis, which could be therapeutically targeted.