Abstract 20689: A Metabolic Basis for Right Ventricular Angiogenesis
In pulmonary arterial hypertension (PAH), after a short compensatory phase, the right ventricle (RV) decompensates by an unknown mechanism; decreased angiogenesis may play a role. Mitochondria, which regulate cell metabolism and O2 sensing, can directly inhibit HIF-1α (and thus angiogenesis) by mitochondrial reactive oxygen species (mROS) and by providing prolyl-hydroxylases substrates (α-ketoglutarate). The glycolytic environment in cancer (even under normoxia) is associated with HIF activation. Since the hypertrophied myocardium is also glycolytic, we hypothesized that a metabolic remodeling might regulate angiogenesis and mark the transition from a compensated RV (CRV) to a decompensated RV (DRV). We studied serial RV mitochondrial/HIF-1α activity and angiogenesis in monocrotaline (MCT)-induced PAH rats, where the first 3wks are characterized by CRV, with increased morbidity and mortality (DRV function) beginning at 4 and peaking at 6wks. PAH (decreased PA acceleration time) was associated with RV hypertrophy (RV/LV+Septum). Compared to control, CRV (2–3 wks-MCT) exhibited increased mitochondrial potential (TMRM), decreased mROS (MitoSOX), decreased α-ketoglutarate, activation of HIF-1α (immunohistochemistry), increased expression of HIF-1α regulated chemokines (VEGF, SDF1), increased ckit+ stem cell recruitment and increased RV glucose uptake (in vivo PET). This resulted in increased RV capillary density (Lectin). In 6wk-MCT (DRV) there was increased mROS, decreased HIF-1α activity, and decreased capillary density, compared to CRV. Uncoupling protein-2 (UCP2), which increases mROS by uncoupling mitochondria, was induced at 4 wks, potentially explaining the disruption of the pro-angiogenic metabolic response and the suppression of HIF and angiogenesis. The UCP2-promoted decreased capillary density in the setting of persistent RVH may explain the RV failure due to ischemia.
- © 2010 by American Heart Association, Inc.