2. Academic Validation
  3. Myeloid Cell Derived IL1β Contributes to Pulmonary Hypertension in HFpEF

Myeloid Cell Derived IL1β Contributes to Pulmonary Hypertension in HFpEF

  • Circ Res. 2023 Nov 10;133(11):885-898. doi: 10.1161/CIRCRESAHA.123.323119.
Vineet Agrawal 1 2,  Jonathan A Kropski 3,  Jason J Gokey 3,  Elizabeth Kobeck 1,  Matthew B Murphy 4,  Katherine T Murray 1 4,  Niki L Fortune 3,  Christy S Moore 1,  David F Meoli 1 2,  Ken Monahan 1,  Yan Ru Su 1,  Thomas Blackwell 1,  Deepak K Gupta 1,  Megha H Talati 1,  Santhi Gladson 1,  Erica J Carrier 1,  James D West 1,  Anna R Hemnes 1
Affiliations

Affiliations

  • 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.
PMID: 37929582 DOI: 10.1161/CIRCRESAHA.123.323119
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 Nγ-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: Nγ-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 Nγ-nitro-L-arginine methyl ester/high-fat diet-treated mice, and IL-1β depletion also attenuated PH in Nγ-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.

Keywords

cytokines; heart failure; hypertension, pulmonary; macrophages; myeloid cells.

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