Myeloid Cell Derived IL1β Contributes to Pulmonary Hypertension in HFpEF

Author:

Agrawal Vineet12ORCID,Kropski Jonathan A.3ORCID,Gokey Jason J.3ORCID,Kobeck Elizabeth1,Murphy Matthew B.4,Murray Katherine T.14ORCID,Fortune Niki L.3,Moore Christy S.1,Meoli David F.12,Monahan Ken1ORCID,Ru Su Yan1,Blackwell Thomas1,Gupta Deepak K.1,Talati Megha H.1,Gladson Santhi1,Carrier Erica J.1ORCID,West James D.1,Hemnes Anna R.1ORCID

Affiliation:

1. Division of Cardiovascular Medicine (V.A., E.K., K.T.M., D.F.M., K.M., Y.R.S., D.K.G.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.

2. Tennessee Valley Healthcare System Nashville Veteran Affairs Hospital (V.A., D.F.M.).

3. Division of Pulmonary, Allergy, and Critical Care (J.A.K., J.J.G., C.S.M., T.B., M.H.T., S.G., E.J.C., J.D.W., A.R.H., N.L.F.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.

4. Division of Clinical Pharmacology (M.B.M., K.T.M., K.T.M.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.

Abstract

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 γ -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-1β (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-1β antibody were utilized to deplete macrophages and IL-1β, respectively, to assess their impact on pulmonary vascular remodeling in HFpEF in mouse models. RESULTS: N γ -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-1β in mouse and human plasma. Finally, clodronate liposome treatment in mice prevented PH in N γ -nitro-L-arginine methyl ester/high-fat diet–treated mice, and IL-1β depletion also attenuated PH in N γ -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-1β as an important contributor to PH in HFpEF.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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