Critical Role for the Advanced Glycation End‐Products Receptor in Pulmonary Arterial Hypertension Etiology

Abstract

BackgroundPulmonary arterial hypertension (PAH) is a vasculopathy characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and suppressed apoptosis. This results in both increase in pulmonary arterial pressure and pulmonary vascular resistance. Recent studies have shown the implication of the signal transducer and activator of transcription 3 (STAT3)/bone morphogenetic protein receptor 2 (BMPR2)/peroxisome proliferator‐activated receptor gamma (PPARγ) in PAH. STAT3 activation induces BMPR2 downregulation, decreasing PPARγ, which both contribute to the proproliferative and antiapoptotic phenotype seen in PAH. In chondrocytes, activation of this axis has been attributed to the advanced glycation end‐products receptor (RAGE). As RAGE is one of the most upregulated proteins in PAH patients' lungs and a strong STAT3 activator, we hypothesized that by activating STAT3, RAGE induces BMPR2 and PPARγ downregulation, promoting PAH‐PASMC proliferation and resistance to apoptosis.Methods and ResultsIn vitro, using PASMCs isolated from PAH and healthy patients, we demonstrated that RAGE is overexpressed in PAH‐PASMC (6‐fold increase), thus inducing STAT3 activation (from 10% to 40% positive cells) and decrease in BMPR2 and PPARγ levels (>50% decrease). Pharmacological activation of RAGE in control cells by S100A4 recapitulates the PAH phenotype (increasing RAGE by 6‐fold, thus activating STAT3 and decreasing BMPR2 and PPARγ). In both conditions, this phenotype is totally reversed on RAGE inhibition. In vivo, RAGE inhibition in monocrotaline‐ and Sugen‐induced PAH demonstrates therapeutic effects characterized by PA pressure and right ventricular hypertrophy decrease (control rats have an mPAP around 15 mm Hg, PAH rats have an mPAP >40 mm Hg, and with RAGE inhibition, mPAP decreases to 20 and 28 mm Hg, respectively, in MCT and Sugen models). This was associated with significant improvement in lung perfusion and vascular remodeling due to decrease in proliferation (>50% decrease) and BMPR2/PPARγ axis restoration (increased by ≥60%).ConclusionWe have demonstrated the implications of RAGE in PAH etiology. Thus, RAGE constitutes a new attractive therapeutic target for PAH.

Role for DNA Damage Signaling in Pulmonary Arterial Hypertension

“…35 Although not explored in the present study, other environmental stresses could also contribute to the increased level of DNA damage in PAH. For example, elevated levels of circulating S100A4, which is upregulated in PAH 36 and is responsible for the advanced glycation end products receptor activation, 37 is implicated in both DNA damage 38 and PAH. 37 It is possible that PARP-1 activation is a common denominator for diverse conditions that cause DNA damage in PAH, making it an attractive therapeutic target.…”

“…For example, elevated levels of circulating S100A4, which is upregulated in PAH 36 and is responsible for the advanced glycation end products receptor activation, 37 is implicated in both DNA damage 38 and PAH. 37 It is possible that PARP-1 activation is a common denominator for diverse conditions that cause DNA damage in PAH, making it an attractive therapeutic target. Although our findings support the implication of DNA damage in PARP activation in PAH, inflammation itself may further contribute to PARP-1 activation (Figure 7).…”

Bromodomain-Containing Protein 4

“…34 This suggests that BRD4-dependent regulation of p21 in PAH may be Myc independent. It was suggested in the literature that peroxisome proliferator-activated receptor γ, another key factor in PAH physiopathology, 35,36 could regulate p21 expression. 37,38 Thus, p21 expression could also be triggered through regulation of this signaling pathway.…”

A Sex-Specific MicroRNA-96/5-Hydroxytryptamine 1B Axis Influences Development of Pulmonary Hypertension

“…BMPR-II expression is reduced in the hypoxic mouse, the monocrotaline rat, and the Sugen/ hypoxic rat (4,54,55). Here, we used the hypoxic mouse model of PH, which produces a robust disease phenotype, including decreased BMPR-II signaling.…”