Myeloid Cell Derived IL1 Contributes to Pulmonary Hypertension in HFpEF

BACKGROUND:Pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are poorly understood. We sought to determine whether a well-accepted murine model of HFpEF also displays features of PH, and we sought to identify pathways that might drive early remodeling of the pulmonary vasculature in HFpEF.METHODS:Eight-week-old male and female C57BL/6J mice received either N gamma-nitro-L-arginine methyl ester and high-fat diet or control water and diet for 2, 5, and 12 weeks. The db/db mice were studied as a second model of HFpEF. Early pathways regulating PH were identified by bulk and single-cell RNA sequencing. Findings were confirmed by immunostain in lungs of mice or lung slides from clinically performed autopsies of patients with PH-HFpEF. ELISA was used to verify IL-1 beta (interleukin-1 beta) in mouse lung, mouse plasma, and also human plasma from patients with PH-HFpEF obtained at the time of right heart catheterization. Clodronate liposomes and an anti-IL-1 beta antibody were utilized to deplete macrophages and IL-1 beta, respectively, to assess their impact on pulmonary vascular remodeling in HFpEF in mouse models.RESULTS:N gamma-nitro-L-arginine methyl ester/high-fat diet-treated mice developed PH, small vessel muscularization, and right heart dysfunction. Inflammation-related gene ontologies were overrepresented in bulk RNA sequencing analysis of whole lungs, with an increase in CD68+ cells in both murine and human PH-HFpEF lungs. Cytokine profiling showed an increase in IL-1 beta in mouse and human plasma. Finally, clodronate liposome treatment in mice prevented PH in N gamma-nitro-L-arginine methyl ester/high-fat diet-treated mice, and IL-1 beta depletion also attenuated PH in N gamma-nitro-L-arginine methyl ester/high-fat diet-treated mice.CONCLUSIONS:We report a novel model for the study of PH and right heart remodeling in HFpEF, and we identify myeloid cell-derived IL-1 beta as an important contributor to PH in HFpEF.