ABSTRACT
Pheochromocytomas are neural crest-derived tumors that arise from inherited or sporadic mutations in at least six independent genes. The proteins encoded by these multiple genes regulate distinct functions. We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced oxidoreductase is detected in all three of these tumor types, together with an angiogenesis/hypoxia profile typical of VHL dysfunction. The oxidoreductase defect, not previously detected in VHL-null tumors, is explained by suppression of the SDHB protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1alpha. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1alpha activity in tumors.
ABSTRACT
CONTEXT: A history of gestational diabetes (GDM) significantly increases the risk of developing type 2 diabetes, an independent risk factor for cardiovascular disease (CVD). It is not known whether nondiabetic women with prior GDM are also at increased risk of CVD. OBJECTIVE: The aim of this study was to compare biochemical and hemodynamic surrogate markers of CVD in nondiabetic women with and without a history of GDM who were at least 1 yr post delivery. DESIGN: This was a single center cross-sectional study. SETTING: The study was performed in an academic referral center. SUBJECTS: Forty-eight premenopausal healthy women with a history of GDM (n = 25) or a history of normal pregnancy (n = 23) were studied in the follicular phase of the menstrual cycle. MAIN OUTCOME MEASURES: The main outcome measures were: 1) inflammatory markers associated with CVD including C-reactive protein, IL-6, and plasminogen activator inhibitor-1; 2) the adipokine adiponectin; and 3) conduit vessel stiffness. RESULTS: When compared to normal controls, women with prior GDM had higher mean levels of C-reactive protein (3.58 +/- 3.86 vs. 0.52 +/- 0.16 mg/liter; P < 0.001), IL-6 (1.81 +/- 1.04 vs. 0.99 +/- 0.52 pg/ml; P = 0.001), plasminogen activator inhibitor-1 (29.6 +/- 17.6 vs. 16.5 +/- 14.0 ng/ml; P = 0.001), and lower levels of adiponectin (8.9 +/- 3.9 vs. 15.9 +/- 7.3 microg/ml; P = 0.001). Women with prior GDM also had significantly (P
