Histologic and Proteomic Remodeling of the Pulmonary Veins and Arteries in a Porcine Model of Chronic Pulmonary Venous Hypertension

Au, Fayyaz; Ms, Sabbah; Dasari, Surendra; Lg, Griffiths; Hm, DuBrock; Mc, Charlesworth; Ba, Borlaug; Sm, Jenkins; Wd, Edwards; Redfield, MM

doi:10.1101/2021.03.26.437051

Cited by 2 publications

(1 citation statement)

References 59 publications

(64 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3,22 Our study adds to the growing list of available models that approximate features of pathological pulmonary vascular remodeling in HFpEF. [23][24][25] The L-NAME/ HFD model has several distinct advantages in that it is technically straightforward to implement, replicates known deficits in nitric oxide (NO) and protein kinase G (PKG) signaling from human studies of HFpEF, 26,27 recapitulates many extracardiac features of HFpEF, including metabolic disease that is prominent in the human condition, 28 and is amenable to further mechanistic studies. Using a discovery-based approach, our study found inflammatory pathways to be altered in the remodeling lung of PH-HFpEF mice.…”

Section: Discussionmentioning

confidence: 99%

Myeloid Cell Derived IL1β Contributes to Pulmonary Hypertension in HFpEF

Agrawal,

Kropski,

Gokey

et al. 2023

Circulation Research

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Myeloid Cell Derived IL1β Contributes to Pulmonary Hypertension in HFpEF

Agrawal,

Kropski,

Gokey

et al. 2023

Circulation Research

View full text Add to dashboard Cite

show abstract

Proteomic Pathways across Ejection Fraction Spectrum in Heart Failure: an EXSCEL Substudy

Peters

Nguyen

Green

et al. 2023

Preprint

View full text Add to dashboard Cite

Of N=1199 EXSCEL participants with prevalent HF, 284 (24%), 704 (59%) and 211 (18%) had HFpEF, HFmrEF and HFrEF, respectively. Eight PCA protein factors and 221 individual proteins within these factors differed significantly across the three EF groups. Levels of the majority of proteins (83%) demonstrated concordance between HFmrEF and HFpEF, but higher levels in HFrEF, predominated by the domain of extracellular matrix regulation, e.g. COL28A1 and tenascin C [TNC]; p<0.0001. Concordance between HFmrEF and HFrEF was observed in a minority of proteins (1%) including MMP-9 (p<0.0001). Biologic pathways of epithelial-mesenchymal transition, ECM receptor interaction, complement and coagulation cascades, and cytokine receptor interaction demonstrated enrichment among proteins with the dominant pattern, i.e. HFmrEF-HFpEF concordance. Baseline levels of 208 (94%) of the 221 proteins were associated with time-to-incident HF hospitalization including domains of extracellular matrix (COL28A1, TNC), angiogenesis (ANG2, VEGFa, VEGFd), myocyte stretch (NT-proBNP), and renal function (cystatin-C). Change in levels of 10 of the 221 proteins from baseline to 12 months (including increase in TNC) predicted incident HF hospitalization (p<0.05). Levels of 30 of the 221 significant proteins (including TNC, NT-proBNP, ANG2) were reduced differentially by EQW compared with placebo (interaction p<0.0001).

show abstract

Histologic and Proteomic Remodeling of the Pulmonary Veins and Arteries in a Porcine Model of Chronic Pulmonary Venous Hypertension

Cited by 2 publications

References 59 publications

Myeloid Cell Derived IL1β Contributes to Pulmonary Hypertension in HFpEF

Myeloid Cell Derived IL1β Contributes to Pulmonary Hypertension in HFpEF

Proteomic Pathways across Ejection Fraction Spectrum in Heart Failure: an EXSCEL Substudy

Contact Info

Product

Resources

About