499 Myocardial Perfusion Pressure in Patients With Coronary Artery Disease and Hypertension With and Without Diabetes Mellitus: Implications for Diastolic Blood Pressure Targets in Hypertension Management

Abstract

vasculopathy characterized by enhanced pulmonary artery smooth muscle cells (PASMC) proliferation and suppressed apoptosis. This results in both increase in pulmonary arterial pressure and pulmonary vascular remodeling. Recent studies have shown the implication of different transcription factors and proteins such as signal of transducer and activator of transcription 3 (STAT3), bone morphogenetic protein receptor 2 (BMPR2) and peroxisome proliferatoractivated receptor gamma (PPARa) in the etiology of PAH. Indeed, the activation of STAT3 induces BMPR2 downregulation contributing to the decrease in PPARa activity. In chondrocytes, the activation of this axis has been attributed to the advanced glycation endproducts receptor (RAGE). In a PAH proteomic study, RAGE has been demonstrated as one of the most upregulated protein in the PAH patients’ lungs. Thus, we hypothesized that by activating STAT3, RAGE induces BMPR2 and PPARa downregulation promoting PAH-PASMC proliferation and resistance to apoptosis in PAH. METHODS/RESULTS: We confirmed on human PAH lung biopsies that RAGE is overexpressed (n 5; qRT-PCR). In vitro, using PASMC isolated from PAH and healthy patients (n 3), we demonstrated that RAGE is overexpressed in PAH-PASMC compare to healthy PASMC. Its upregulation induces STAT3 activation and BMPR2 and PPARa decrease (qRT-PCR; western blot). The activation of the RAGE/STAT3/BMPR2/PPARa axis promotes PAHPASMC proliferation (Ki67) and suppresses apoptosis (TUNEL). This phenotype was totally reversed upon RAGE inhibition (by siRNA) or PPARa activation (by rosiglitazone). Furthermore, control cells treated with a RAGE agonist (S100A4 peptide) or with a PPARa antagonist (W9662) have a proliferative phenotype, mimicking the pathology. The S100A4 proliferative phenotype is reversed when PPARa is activated and we also demonstrated that PPARa is a downstream target of RAGE. In vivo, RAGE inhibition (siRNA nebulization i.t.) in rats with monocrotaline and sugen-induced PAH had decreased mean PA pressure (catheterization and Doppler echography) and right ventricular hypertrophy (M-mode ultrasound, n 8 per group). This decrease in PAH was associated with a significant improvement in lung perfusion measured by CT-angiogram and decreased PA wall thickness. Decrease in PA remodeling is associated with a decrease in both proliferation (Ki67) and resistance to apoptosis (TUNEL), associated with RAGE/STAT3/BMPR2/PPARa axis deregulation. Thus, we demonstrated for the first time that RAGE is an upstream regulator of PPARa and that Sugen-induced PAH could be reversed by protein inhibition. CONCLUSION: We demonstrated the implication of RAGE in the etiology of PAH. Moreover, we showed that RAGE constitutes a new and attractive therapeutic target for PAH. Featured Research