Crucial role of RAGE in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension

Abstract

BackgroundPulmonary vascular remodeling of pulmonary arterial hypertension (PAH) is characterized by an inappropriate increase of vascular cells. The receptor for advanced glycation end products (RAGE) is a type I single-pass transmembrane protein belonging to the immunoglobulin superfamily and is involved in a broad range of hyperproliferative diseases. RAGE is also implicated in the etiology of PAH and is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with PAH. We examined the role of RAGE in the inappropriate increase of PASMCs in patients with PAH.Methods and resultsPASMCs were obtained from 12 patients with PAH including 9 patients with idiopathic PAH (IPAH) and 3 patients with heritable PAH (HPAH) (2 patients with BMPR2 mutation and one patient with SMAD9 mutation) who underwent lung transplantation. Western blot analysis and immunofluorescence staining revealed that RAGE and S100A8 and A9, ligands of RAGE, were overexpressed in IPAH and HPAH-PASMCs in the absence of any external growth stimulus. PDGF-BB (10 ng/mL) up-regulated the expression of RAGE in IPAH and HPAH-PASMCs. PAH-PASMCs are hyperplastic in the absence of any external growth stimulus as assessed by 3H-thymidine incorporation. This result indicates overgrowth characterized by continued growth under a condition of no growth stimulation in PAH-PASMCs. PDGF-BB stimulation caused a higher growth rate of PAH-PASMCs than that of non-PAH-PASMCs. AS-1, an inhibitor of TIR domain-mediated RAGE signaling, significantly inhibited overgrowth characterized by continued growth under a condition of no growth stimulation in IPAH and HPAH-PASMCs (P<0.0001). Furthermore, AS-1 significantly inhibited PDGF-stimulated proliferation of IPAH and HPAH-PASMCs (P<0.0001).ConclusionsRAGE plays a crucial role in the inappropriate increase of PAH-PASMCs. Inhibition of RAGE signaling may be a new therapeutic strategy for PAH.

Calprotectin in Lung Diseases

“…It has only been reported that RAGE and S100A8/A9 are overexpressed in pulmonary artery smooth muscle cells in the absence of any external growth stimulus in patients with either heritable or idiopathic pulmonary arterial hypertension. Nevertheless, further studies are needed to clarify the precise role of S100A8/A9 in the pathophysiology of pulmonary arterial hypertension [205]. Figure 1 illustrates the structure of calcium loaded CLP and summarizes the proposed biological functions.…”

SARS-CoV-2-mediated inflammatory response in lungs: should we look at RAGE?

“…Although RAGE has been defined as a specific marker of AT1 cells, after cell injury [23], RAGE may also be expressed in type 2 alveolar epithelial (AT2) cells [24]. In addition to lung epithelium, RAGE expression has also been noted in many crucial cell types in lung physiology, such as vascular smooth muscle cells [25], airway smooth muscle cells [26], and endothelial cells [27].…”

World Trade Center-Cardiorespiratory and Vascular Dysfunction: Assessing the Phenotype and Metabolome of a Murine Particulate Matter Exposure Model

“…Literature suggests a causative role Our present study also demonstrates that PM-exposed mice had significantly elevated sRAGE in BAL and plasma which is in line with our prior findings that RAGE is pivotal to WTC-PM lung injury 16 . RAGE has been implicated in cardiopulmonary diseases, such as pulmonary arterial hypertension 35 . Further, RAGE is overexpressed in smooth muscle cells of patients with both idiopathic and heritable pulmonary arterial hypertension.…”