LAUSR

RATIONALE Pulmonary hypertension (PH) due to left heart disease (PH-LHD), or Group2-PH, is the most prevalent form of PH worldwide. PH-LHD is often associated with metabolic syndrome (MetS). In 12-13% of cases, patients with PH-LHD display vascular remodeling of pulmonary arteries associated with poor prognosis. Unfortunately, the underlying mechanisms remain unknown; PH-targeted therapies for this group are non-existent and the development of a new preclinical model is crucial. Among the numerous pathways dysregulated in MetS, inflammation plays also a critical role in both PH and vascular remodeling. OBJECTIVE We hypothesized that MetS and Inflammation may trigger the development of vascular remodeling in Group 2 PH. METHODS AND RESULTS Using supra-coronary aortic banding (SAB), we induced diastolic dysfunction in rats. Then MetS, created by the combination of a high-fat diet (HFD) and olanzapine. We used metformin treatment and anti-IL-6 antibodies to inhibit the IL-6 pathway. Compared to sham conditions, only SAB+MetS rats developed precapillary PH, as measured by both echocardiography and right/left heart catheterization. PH in SAB+MetS was associated with macrophage accumulation, and increased IL-6 production in lung. PH was also associated with STAT3 activation and increased proliferation of pulmonary artery smooth muscle cells (PASMC), which contributes to remodeling of distal PA. We reported macrophage accumulation, increased IL-6 levels and STAT3 activation in the lung of Group 2 PH patients. In vitro, IL-6 activates STAT3 and induces human-PASMC proliferation. Metformin treatment decreased inflammation, IL-6 levels, STAT3 activation and human-PASMC proliferation. In vivo, in the SAB+MetS animals, reducing IL-6, either by anti-IL-6 antibody or metformin treatment, reversed pulmonary vascular remodeling and improve PH-LHD. CONCLUSIONS We developed a new preclinical model of Group2-PH by combining MetS with LHD. We showed that MetS exacerbates Group 2 PH. We provided evidence for the importance of the IL-6-STAT3 pathway in our experimental model of Group2-PH and human patients.