Abstract 15969: Activation of RAGE/STAT3 Axis by Advanced Glycation Endproducts in Vascular Remodeling Diseases
Vascular remodeling diseases (VRD), including pulmonary arterial hypertension, are characterized by enhanced vascular smooth muscle cells (VSMC) proliferation and resistance to apoptosis. We described that the sustainability of this phenotype is associated with a decrease of Kv1.5, increasing VSMC [Ca2+]i and promoting proliferation as well as a mitochondrial membrane potential (Δψm) hyperpolarization, suppressing apoptosis. Nonetheless the mechanisms accounting for these abnormalities remain elusive. By activating the advanced glycation endproducts (AGE) receptor (RAGE), AGE molecule like carboxymethyl lysine (CML), promotes cell proliferation in cancer by activating the transcription factor STAT3. Interestingly, plasmatic levels of CML are increased in patients with VRD, which led to hypothesize that AGE molecule like CML promotes cell proliferation, resistance to apoptosis in vascular remodeling diseases by activating RAGE/STAT3 axis.
Results: Circulating CML (ELISA) are increased in VRD-patients (n=33; p<0.05) compare to control (n=23). In vitro, freshly isolated human VSMC exposed to CML for 48h (50ng/ml which is a dose similar to ones found in VRD patients) had 1) activated STAT3 (increased P-STAT3/STAT3 ratio and P-STAT3 nuclear translocation); 2) decreased Kv1.5 (n=200, p<0.05, immunofluorescence) 3) increased [Ca2+]i (n=100; p<0.05, confocal microscopy using FLUO-3) increasing VSMC proliferation (n=200; p<0.05 PCNA, Ki-67); 4) hyperpolarized mitochondria through a STAT3/Bad-dependent mechanism (n=150; p<0.05, confocal microscopy using TMRM), decreasing apoptosis (n=250; p<0.05 TUNEL, annexinV). Inhibiting RAGE or STAT3 (siRNA) reverses these abnormalities. Finally, in vivo RAGE inhibition by siRNA prevents and reverses carotid artery remodeling in a rat carotid injury model.
Conclusion: Increased circulating CML levels accounts for many features of VRD including VSMC proliferation and resistance to apoptosis by the activation of RAGE/STAT3 axis. Molecules aimed to inhibit RAGE could be of a great therapeutic interest for the treatment of VRD including pulmonary arterial hypertension and carotid stenosis.
- © 2010 by American Heart Association, Inc.