Multi-omics Analyses Identify Galectin-1 as a Potential Novel Mediator of Heart Failure with Preserved Ejection Fraction in Mice and Humans

Autor: Jean Wassenaar, Duncan Smart, Daniel Fehrenbach, Matthew Dungan, Amanda Doran, Megan Shuey, Meena Madhur
Rok vydání: 2023
Předmět:
Zdroj: Physiology. 38
ISSN: 1548-9221
1548-9213
Popis: Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome where patients present with symptoms of volume overload despite having a normal systolic function. HFpEF is associated with elevation of inflammatory biomarkers, but the precise pathways leading to cardiac dysfunction is not known. In a deoxycorticosterone acetate (DOCA)-salt model of hypertension and HFpEF, we performed CITE-Seq analysis on total leukocytes isolated from the heart, which revealed significant differential gene expression primarily in the myeloid population. We then took the top 20 genes that were differentially expressed between myeloid cells from DOCA-salt vs sham treated mice and performed a genetic analysis called PrediXcan in Vanderbilt’s DNA databank, BioVU. Genetically predicted expression of two genes were associated with a HFpEF phenotype in humans. Of these, the gene encoding galectin 1, Lgals1, had the lowest p-value (0.02) and highest beta coefficient (0.32) corresponding to an odds ratio for HFpEF of 1.38. The role of galectin-1 in heart failure is unknown, we hypothesized that overexpression of Lgals1 exacerbates HFpEF. We found that siRNA knockdown of Lgals1 in bone marrow derived macrophages stimulated with lipoprotein saccharide and IFNγ, they expressed significantly more inflammatory genes such as IL-1α (p 0.05 using Student’s t-test for all parameters measured, n=10-12). One hypothesis for this negative result is that Lgals1 is ubiquitously expressed, and a total body knockout may have compensatory mechanisms. We therefore created Lgals1 floxed mice and future studies will determine the effect of macrophage specific deletion of galectin-1 on HFpEF. In conclusion, while multi-omics approaches in mice and humans identify galectin-1 as a novel mediator of HFpEF, further studies in mice are needed to confirm its roles as a potential therapeutic target. 1R01HL161212-01A1, 19EIA34480023,,19IPLOI34760558, and 1T32HL144446-01 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Databáze: OpenAIRE
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