Abstract 19228: Lack of Uncoupling Protein 2 (UCP2) Reduces Mitochondrial Calcium Uptake from the Endoplasmic Reticulum (ER), Triggering Mitochondrial Suppression and Pulmonary Hypertension (PHT)
A metabolic shift from glucose oxidation to glycolysis due to suppressed mitochondrial function contributes to the hyperproliferation and resistance to apoptosis in resistance pulmonary arteries (PA) in PHT. Disruption of the ER-mitochondria unit, which can result from many PHT-triggers including hypoxia, prevents the transfer of ER Ca2+ to mitochondria, reducing the activity of Ca2+-sensitive mitochondrial enzymes and causing mitochondrial suppression. Emerging links between PHT and insulin resistance suggest a global metabolic dysfunction. The mitochondrial protein UCP2 is implicated in the uptake of ER-derived Ca2+ and loss-of-function UCP2 polymorphisms are associated with insulin resistance/obesity. We hypothesized that reduced UCP2-mediated mitochondrial Ca2+ uptake suppresses mitochondrial function and causes PHT. UCP2 is expressed in PA smooth muscle cells (PASMCs) from wild-type (WT), but not knockout (KO) mice. KO-PASMCs had lower mitochondrial Ca2+ levels than WT-PASMCs, at baseline and during histamine-stimulated ER Ca2+ release (FRET-imaging), despite intact ER-mitochondrial morphology (electron microscopy). In keeping with reduced mitochondrial Ca2+, KO-PASMCs had mitochondrial hyperpolarization, lower activity of Ca2+-sensitive mitochondrial enzymes, reduced mitochondrial reactive oxygen species and resistance to apoptosis. UCP2 KO-mice (which have an apparently normal phenotype) had a modest, but significant elevation in mean PA pressure (catheterization; 26±2 vs. 19±1 mmHg), total pulmonary resistance (1.37±.14 vs. 0.89±0.07 mmHg ml-1 min), %medial thickness, PASMC proliferation (% Ki67-positive), and resistance PA muscularization (n=6, p<0.05 for all). Chronic Hypoxia increased PA pressure in WT-mice to the level of the normoxic UCP2 KO-mice. However the UCP2 KO-mice were resistant to further exacerbation of PHT in vivo or hypoxia-induced PASMC changes in vitro. Since in hypoxia-induced PHT the ER-mitochondria unit is disrupted, the loss of UCP2 does not have additional effects. We conclude that lack of UCP2 causes mitochondrial suppression in PASMC and predisposes to PHT. UCP2 polymorphisms may predispose to PHT and potentially underlie the unexplained systemic metabolic abnormalities in PHT.
- © 2012 by American Heart Association, Inc.