The Spp1+ macrophages in HFpEF pathogenesis
Description: Heart failure with preserved ejection fraction (HFpEF) is tightly associated with obesity and metabolic syndrome (MetS), and chronic inflammation has been recognized as a major contributor to HFpEF pathogenesis. However, the underlying mechanisms remain elusive. Macrophages are a heterogenous group of cells that play diversified roles in the heart. By analyzing single-cell RNA Sequencing (scRNA-Seq) data, we discovered an enrichment of Spp1+ macrophages in the ventricles of HFpEF mice. These cells are mainly recruited from the bone marrow and expand in MetS-associated pathologies. To better understand their function, we assessed the most dysregulated pathways in these cells and found that senescence-associated pathways were specifically upregulated. Additionally, we found that Spp1 knockout mice developed an attenuated HFpEF phenotype, suggesting that Spp1 might be pathogenic. To test the hypothesis that Spp1 contributes to HFpEF pathogenesis by promoting macrophage senescence, we proposed three specific aims. In Aim 1, we will determine the contribution of macrophage-secreted Spp1 to HFpEF pathogenesis by either grafting mice with Spp1-deficient bone marrow cells or using an Spp1 neutralizing antibody. We will assess the impact of Spp1 deficiency on the HFpEF phenotype and underlying pathology. In Aim 2, we will elucidate the role of Spp1 in macrophage senescence by gain- and loss-of-function approaches using cultured cells. In Aim 3, we will determine the role of senescent macrophages in HFpEF pathology by testing the therapeutic effects of senolytic drugs, which eliminate senescent cells. Our study will provide critical insights into the function of specific macrophage subsets in HFpEF pathogenesis which may serve as novel therapeutic targets.
Funder: American Heart Association
Amount: $165,900
Funding type: training
Funder scheme: Diversity Supplement
Start date: 2025-07-01
End date: 2027-06-30
Investigators: Claudia Munoz Rodriguez, Claudia Munoz Rodriguez
Institution: The University of Texas Southwestern Medical Center (UT Southwestern)
Funded outputs count: 0
Funder award ID: 25DIVSUP1471725
OpenAlex ID: G8115641926