Ectopic upregulation of membrane-bound IL6R drives vascular remodeling in pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is characterized by a progressive accumulation of pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterioles leading to the narrowing of the lumen, right heart failure, and death. Although most studies have supported the notion of a role for IL-6/glycoprotein 130 (gp130) signaling in PAH, it remains unclear how this signaling pathway determines the progression of the disease. Here, we identify ectopic upregulation of membrane-bound IL-6 receptor (IL6R) on PA-SMCs in PAH patients and in rodent models of pulmonary hypertension (PH) and demonstrate its key role for PA-SMC accumulation in vitro and in vivo. Using Sm22a-Cre Il6rfl/fl, which lack Il6r in SM22A-expressing cells, we found that these animals are protected against chronic hypoxia-induced PH with reduced PA-SMC accumulation, revealing the potent pro-survival potential of membrane-bound IL6R. Moreover, we determine that treatment with IL6R-specific antagonist reverses experimental PH in two rat models. This therapeutic strategy holds promise for future clinical studies in PAH.

Anaemia, iron homeostasis and pulmonary hypertension: a review

“…NF-kappaB is an iron-dependent transcription factor, which per se induces IL1, IL6 and TNFalpha synthesis. Elevated serum IL6 levels, alterations of STAT3 signalling, ectopic upregulation of the IL6R in PASMCs and IL6 promoted perivascular infiltration of macrophages were all associated with the development of PH [48,67]. Accordingly, hypoxia-induced TNFalpha expression is also linked to PH.…”

Therapeutic effect of pirfenidone in the sugen/hypoxia rat model of severe pulmonary hypertension

“…1A, B) (14). At the end of these protocols, transthoracic echocardiography and right heart catheterization were performed as previously described (15,16). Briefly, animals were anesthetized with isoflurane.…”

“…Preoperative echocardiography was performed in these control patients to rule out PH, and the absence of tumoral infiltration was retrospectively established in all tissue sections by histopathologic analysis. Briefly, as previously described (16)(17)(18), small pieces of freshly isolated arteries were cultured in Dulbecco modified Eagle medium supplemented with 15% fetal calf serum (FCS), 2 mM L-glutamine, and antibiotics. The isolated pulmonary PA-SMCs were strongly positive for a-smooth muscle actin, smooth muscle-specific SM22 protein, and calponin, and negative for von Willebrand factor and CD31.…”

“…Cells and tissues were homogenized and sonicated in RIPA buffer containing protease and phosphatase inhibitors, and 30 mg of protein was used to detect tenascin-C, collagen (col)1A, colV, fibronectin, phosphoSmad2/3 (pSmad2/3), FoxO1, nitrotyrosine, superoxide dismutase 2, p21, catalase, connective tissue growth factor (CTGF), and b-actin (16)(17)(18)(19). Immunohistochemistry and immunocytofluorescent staining for proliferating cell nuclear antigen (PCNA), CD45 (lymphocyte common antigen), CD68 (macrophage), 8-oxo-deoxyguanosine (8-oxo-dG), FoxO1, pSmad2/3, von Willebrand factor, and SM22 were performed in human and rat lung paraffin-embedded sections (16)(17)(18)(19). Briefly, lung sections were deparaffined and stained with hematoxylin and eosin (MilliporeSigma, St. Louis, MO, USA), Picrosirius red, or Masson trichrome, or they were incubated with retrieval buffer.…”

“…Both PA-SMC proliferation and migration played major roles in the progression of pulmonary vascular remodeling in PAH (neointima formation and media hypertrophy) (16,17). We thus next examined the effect of PFD treatment on the proliferative and migratory potentials of cultured PA-SMCs derived from iPAH patients.…”