Neutralization of CXCL12 attenuates established pulmonary hypertension in rats
Authors: Christophe Guignabert
Dominique Bonnet
Jean-Luc Galzi
Marc Humbert
Ly Tu
Laurent Savale
Raphaël Thuillet
Amélie Cumont
Marcel Hibert
Alice Huertas
Carole Phan
Claire Marsol
Jennifer Bordenave
Nelly Frossard
Journal: Cardiovascular Research (2020)
Discipline: CLINICAL MEDICINE
Keywords: Animal model; Chemokine; Pulmonary arterial hypertension; Stromal cell-derived factor 1; Therapeutic target
Affiliations: INSERM UMR_S 999, Hôpital Marie Lannelongue, 133 Avenue de la Résistance, 92350 Le Plessis-Robinson, France., Université Paris-Sud and Université Paris-Saclay, 94270 Le Kremlin-Bicêtre, France., Laboratoire d'Innovation Thérapeutique, UMR7200 CNRS/Université de Strasbourg and LabEx MEDALIS, Faculté de Pharmacie, 74 route du Rhin, 67412 Illkirch, France., AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France., Biotechnologie et Signalisation Cellulaire, Ecole Supérieure de Biotechnologie de Strasbourg, UMR 7242 CNRS/Université de Strasbourg, 67400 Illkirch, France.

Abstract:  Aims: The progressive accumulation of cells in pulmonary vascular walls is a key pathological feature of pulmonary arterial hypertension (PAH) that results in narrowing of the vessel lumen, but treatments targeting this mechanism are lacking. The C-X-C motif chemokine 12 (CXCL12) appears to be crucial in these processes. We investigated the activity of two CXCL12 neutraligands on experimental pulmonary hypertension (PH), using two complementary animal models. Methods and results: Male Wistar rats were injected with monocrotaline (MCT) or were subjected to SU5416 followed by 3-week hypoxia to induce severe PH. After PH establishment, assessed by pulsed-wave Doppler echocardiography, MCT-injected or SU5416 plus chronic hypoxia (SuHx) rats were randomized to receive CXCL12 neutraligands chalcone 4 or LIT-927 (100 mg/kg/day), the C-X-C motif chemokine receptor 4 (CXCR4) antagonist AMD3100 (5 mg/kg/day), or vehicle, for 2 or 3 weeks, respectively. At the end of these treatment periods, echocardiographic and haemodynamic measurements were performed and tissue samples were collected for protein expression and histological analysis. Daily treatment of MCT-injected or SuHx rats with established PH with chalcone 4 or LIT-927 partially reversed established PH, reducing total pulmonary vascular resistance, and remodelling of pulmonary arterioles. Consistent with these observations, we found that neutralization of CXCL12 attenuates right ventricular hypertrophy, pulmonary vascular remodelling, and decreases pulmonary artery smooth muscle cell (PA-SMC) proliferation in lungs of MCT-injected rats and SuHx rats. Importantly, CXCL12 neutralization with either chalcone 4 or LIT-927 inhibited the migration of PA-SMCs and pericytes in vitro with a better efficacy than AMD3100. Finally, we found that CXCL12 neutralization decreases vascular pericyte coverage and macrophage infiltration in lungs of both MCT-injected and SuHx rats. Conclusion: We report here a greater beneficial effect of CXCL12 neutralization vs. the conventional CXCR4 blockade with AMD3100 in the MCT and SuHx rat models of severe PH, supporting a role for CXCL12 in the progression of vascular complications in PH and opening to new therapeutic options. 

Retracted: No

PubPeer comments:
 Figure 6A One of the WB (down) dysplays 11 lanes (beta-actin) while the samples are 10. ,