LY-2189102

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.

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.

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.

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.

In recent years, a new target closely linked to a variety of diseases has appeared in the researchers' vision, which is the NLRP3 inflammasome. With the deepening of the study of NLRP3 inflammasome, it was found that it plays an extremely important role in a variety of physiological pathological processes, and NLRP3 inflammasome was also found to be associated with some age-related diseases. It is associated with the development of insulin resistance, Alzheimer's disease, Parkinson's, cardiovascular aging, hearing and vision loss. At present, the only clinical approach to the treatment of NLRP3 inflammasome-related diseases is to use anti-IL-1β antibodies, but NLRP3-specific inhibitors may be better than the IL-1β antibodies. This article reviews the relationship between NLRP3 inflammasome and aging diseases: summarizes some of the relevant experimental results reported in recent years, and introduces the biological signals or pathways closely related to the NLRP3 inflammasome in a variety of aging diseases, and also introduces some promising small molecule inhibitors of NLRP3 inflammasome for clinical treatment, such as: ZYIL1, DFV890 and OLT1177, they have excellent pharmacological effects and good pharmacokinetics.