Role for Runt-related Transcription Factor 2 in Proliferative and Calcified Vascular Lesions in Pulmonary Arterial Hypertension

被引:94
作者
Ruffenach, Gregoire [1 ]
Chabot, Sophie [1 ]
Tanguay, Virginie F. [1 ]
Courboulin, Audrey [2 ,3 ]
Boucherat, Olivier [1 ]
Potus, Francois [1 ]
Meloche, Jolyane [1 ]
Pflieger, Aude [1 ]
Breuils-Bonnet, Sandra [1 ]
Nadeau, Valerie [1 ]
Paradis, Renee [1 ]
Tremblay, Eve [1 ]
Girerd, Barbara [2 ,3 ]
Hautefort, Aurelie [2 ,3 ]
Montani, David [2 ,3 ]
Fadel, Elie [2 ,3 ]
Dorfmuller, Peter [2 ,3 ]
Humbert, Marc [2 ,3 ]
Perros, Frederic [1 ,2 ,3 ]
Paulin, Roxane [1 ]
Provencher, Steeve [1 ]
Bonnet, Sebastien [1 ]
机构
[1] Univ Laval, Dept Med, Quebec Heart & Lung Inst Res Ctr, Pulm Hypertens Res Grp, Quebec City, PQ, Canada
[2] INSERM, UMR S 999, Le Plessis Robinson, France
[3] Univ Paris Sud, Ctr Chirurg Marie Lannelongue, Lab Excellence Rech Medicament & Innovat Therapeu, Le Plessis Robinson, France
基金
加拿大健康研究院;
关键词
vascular remodeling; calcification; hypoxia-inducible factor-1 alpha; pulmonary hypertension; pulmonary artery smooth muscle cells; DNA-DAMAGE; BREAST-CANCER; BONE; CALCIFICATION; PATHWAY; CELLS; MORTALITY; METABOLISM; EXPRESSION; APOPTOSIS;
D O I
10.1164/rccm.201512-2380OC
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
Rationale: Pulmonary arterial hypertension (PAH) is characterized by excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). This is sustained in time by the down-regulation of microRNA (miR)-204. In systemic vascular diseases, reduced miR-204 expression promotes vascular biomineralization by augmenting the expression of the transcription factor Runt-related transcription factor 2 (RUNX2). Implication of RUNX2 in PAH-related vascular remodeling and presence of calcified lesions in PAH remain unexplored. Objectives: We hypothesized that RUNX2 is up-regulated in lungs of patients with PAH, contributing to vascular remodeling and calcium-related biomineralization. Methods: We harvested human lung tissues in which we assessed calcification lesions and RUNX2 expression. We also isolated PASMCs from these tissues for in vitro analyses. Using a bidirectional approach, we investigated the role for RUNX2 in cell proliferation, apoptosis, and calcification capacity. Ectopic delivery of small interfering RNA against RUNX2 was used in an animal model of PAH to evaluate the therapeutic potential of RUNX2 inhibition in this disease. Measurements and Main Results: Patients with PAH display features of calcified lesions within the distal pulmonary arteries (PAs). We show that RUNX2 is up-regulated in lungs, distal PAs, and, primary cultured human PASMCs isolated from PAH and compared with patients without PAH. RUNX2 expression histologically correlates with vascular remodeling and calcification. Using in vitro gain- and loss-of function approaches, we mechanistically demonstrate that miR-204 diminution promotes RUNX2 up-regulation and that sustained RUNX2 expression activates hypoxia-inducible factor-1 alpha, leading to aberrant proliferation, resistance to apoptosis, and subsequent transdifferentiation of PAH-PASMCs into osteoblast-like cells. In the PAH Sugen/hypoxia rat model, molecular RUNX2 inhibition reduces PA remodeling and prevents calcification, thus improving pulmonary hemodynamic parameters and right ventricular function. Conclusions: RUNX2 plays a pivotal role in the pathogenesis of PAH, contributing to the development of proliferative and calcified PA lesions. Inhibition of RUNX2 may therefore represent an attractive therapeutic strategy for PAH.
引用
收藏
页码:1273 / 1285
页数:13
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